Cell and Tissue Biology PDF - Basic Biomedical Sciences I - Case 1

CELL AND TISSUE BIOLOGY SYSTEM COORDINATOR: DR. CLINIA SEGUERRA BLOCK 2 MODULE 1 BASIC BIOMEDICAL SCIENCES I NOT FOR SALE | DO NOT UPLOAD IN ONLIN...

CELL AND TISSUE BIOLOGY SYSTEM COORDINATOR: DR. CLINIA SEGUERRA BLOCK 2 MODULE 1 BASIC BIOMEDICAL SCIENCES I NOT FOR SALE | DO NOT UPLOAD IN ONLINE SITES ------------------------------------------------------------------------------------------------------------------------------------------------------- CASE 1 organelles such as cilia, nerve axons, the mitotic spindles of cells LEVELS OF STRUCTURAL ORGANIZATION undergoing mitosis, and a tangled mass of thin filamentous tubules Chemical level that hold the parts of the cytoplasm and nucleoplasm together in o Interactions among atoms (smallest particle of a substance) and their their respective compartments. Fibrillar proteins are found outside combinations into molecules the cell, especially in the collagen and elastin fibers of connective Cellular level tissue, and elsewhere, such as in blood vessel walls, tendons, and o Also called the molecular level ligaments. o Molecule- smallest particle of a substance that retains its properties  The functional proteins are usually composed of combinations of o Organelle- smallest structure within the cell that performs one or more a few molecules in tubular-globular form. These proteins are mainly specific functions the enzymes of the cell and, in contrast to the fibrillar proteins, are o Cells- basic functional unit of complex organisms. 200 different types often mobile in the cell fluid. Also, many of them are adherent to in the human body membranous structures inside the cell and catalyze specific Tissue level intracellular chemical reactions. For example, the chemical o Group of cells with a similar structure and function reactions that split glucose into its component parts and then o Types: Connective, Muscle, Epithelial, Nervous combine these with oxygen to form carbon dioxide and water while Organ level simultaneously providing energy for cellular function are all o More than 1 type of tissue working together to complete specific tasks catalyzed by a series of protein enzymes. Organ system level o Lipids o Group of organs classified as a unit because they have a common  Lipids are several types of substances that are grouped together function because of their common property of being soluble in fat solvents. o Activities should be coordinated for normal function Especially important lipids are phospholipids and cholesterol, o 11 Organ Systems: Nervous, Integumentary, Circulatory, which together constitute only about 2% of the total cell mass. Urinary/Excretory, Reproductive, Skeletal, Lymphatic, Muscular, Phospholipids and cholesterol are mainly insoluble in water and Respiratory, Endocrine, Digestive therefore are used to form the cell membrane and intracellular Organism level membrane barriers that separate the different cell compartments. o Largest level of organization  In addition to phospholipids and cholesterol, some cells contain o Living thing considered as a whole large quantities of triglycerides, also called neutral fats. In fat cells o 5 kingdoms of organizations: (adipocytes), triglycerides often account for as much as 95% of the  Protista- unicellular eukaryotes (e.g., algae, slime molds) cell mass. The fat stored in these cells represents the body’s main  Fungi- multicellular eukaryotes (e.g., mushrooms) storehouse of energy-giving nutrients that can later be used to  Animalia- multicellular eukaryotes provide energy wherever it is needed in the body.  Plantae- multicellular eukaryotes o Carbohydrates  Monera- prokaryotes; cell walls are made up of peptidoglycan; uses  Carbohydrates play a major role in cell nutrition and, as parts of flagella for movement (e.g., archaebacteria or eubacteria) glycoprotein molecules, have structural functions. Most human cells BASIC ORGANIZATIONAL STRUCTURE OF A TYPICAL CELL do not maintain large stores of carbohydrates; the amount usually Its two major parts are the nucleus and the cytoplasm. The nucleus is averages only about 1% of their total mass but increases to as much separated from the cytoplasm by a nuclear membrane, and the as 3% in muscle cells and, occasionally, to 6% in liver cells. cytoplasm is separated from the surrounding fluids by a cell membrane,  However, carbohydrate in the form of dissolved glucose is always also called the plasma membrane. present in the surrounding extracellular fluid so that it is readily available to the cell. Also, a small amount of carbohydrate is stored Protoplasm, the living substance of the cell, is subdivided into two in cells as glycogen, an insoluble polymer of glucose that can be compartments: the cytoplasm, extending from the plasma membrane depolymerized and used rapidly to supply the cell’s energy needs. to the nuclear envelope, and the karyoplasm, the material forming the contents of the nucleus. o The different substances that make up the cell are collectively called protoplasm. Protoplasm is composed mainly of 5 basic substances- water, electrolytes, proteins, lipids, and carbohydrates. o Water  Most cells, except for fat cells, are comprised mainly of water in a concentration of 70% to 85%.  Many cellular chemicals are dissolved in the water. Others are suspended in the water as solid particulates. Chemical reactions take place among the dissolved chemicals or at the surfaces of the suspended particles or membranes. o Ions  Important ions in the cell include potassium, magnesium, phosphate, sulfate, bicarbonate, and smaller quantities of sodium, chloride, and calcium.  The ions provide inorganic chemicals for cellular reactions and are necessary for the operation of some cellular control mechanisms. NUCLEUS For example, ions acting at the cell membrane are required for the Parts of the nucleus transmission of electrochemical impulses in nerve and muscle fibers. o The nucleus is bounded by a nuclear envelope that participates in o Proteins the organization of the chromatin and controls the movement of  After water, the most abundant substances in most cells are proteins, macromolecules between the nucleoplasm and the surrounding which normally constitute 10% to 20% of the cell mass. These cytoplasm. proteins can be divided into two types, structural proteins and  Its structure consists of two parallel membranes separated by a 10- functional proteins. 30-nm space, the perinuclear cisterna. The outer membrane may  Structural proteins are present in the cell mainly in the form of long have small granules (ribosomes) adhering to its outer surface and it filaments that are polymers of many individual protein molecules. A is often continuous with membrane-bounded tubular elements prominent use of such intracellular filaments is to form extending throughout the cytoplasm (the endoplasmic reticulum). microtubules, which provide the cytoskeletons of cellular   At many sites around the circumference of the nucleus, the inner nucleosome with straight spacer segments of DNA, of varying length, and outer membranes of the nuclear envelope are continuous with between successive nucleosomes. An additional histone H1, is one another, around circular nuclear pores that serve as avenues associated with the connecting segments of the DNA molecule. of communication between the nucleoplasm and the cytoplasm. The  In the interval between cell divisions, the chromosomes are pores are not always uniformly distributed, and their number varies unwound in the form of chromatin. Depending on its transcriptional from a few dozen to several thousand in cell types that are activity, chromatin may be condensed as heterochromatin or metabolically very active. In the nuclear pore, several structures are extended as euchromatin. found so that they are now called nuclear pore complex.  Heterochromatin, a condensed inactive form of chromatin, stains  Parts of the nuclear pore complex deeply with Feulgen stains, which make it visible with the light  Co-axial rings microscope. It is located mostly at the periphery of the nucleus and  Outer ring (Cytoplasmic ring)- facing the cytoplasm comprises almost 90% of the total chromatin of the nucleus.  Inner ring (Nucleoplasmic ring)- facing the nucleoplasm  The remainder of the chromatin scattered throughout the nucleus  Attached to the membrane at the inner and outer rims of the pore and not visible with the light microscope is euchromatin. This are particles arranged in two distinct coaxial rings, about 120 nm represents the active form of chromatin where the genetic material in diameter. Each ring is composed of eight subunits 15-20 nm of the DNA molecules is being transcribed into RNA. Therefore, in diameter. Projecting inward from these subunits are eight heterochromatin is the folded, non-euchromatin that is not being radially arranged spokes that converge at what appears to be a transcribed. central granule or plug. The eight subunits of the rings, their  A vesicular nucleus is a large and pale nucleus because the radial spokes, and connecting links form a structural framework chromatin are extended while a pyknotic nucleus is a small and that imposed on the pore an octagonal symmetry around an axis dark nucleus because chromosomes are condensed. perpendicular to the plane of the nuclear envelope.  Only one of the two X chromosomes in female somatic cells is  Scaffold- forms the major mass of the pore complex. It surrounds transcriptionally active. Microscopic study of interphase nuclei of and entwines the periphery of the pore forming the cytoplasmic cells from females displays a very tightly coiled clump of chromatin, (outer) and nucleoplasmic (inner) ring. This maintains the fusion the sex chromatin (Barr body), which is the inactive counterpart of of the nuclear membrane, supports the transporter, and provides the two X chromosomes. It is randomly determined early in the diffusion channels development, and remains inactive throughout the life.  Transporter- proteinaceous ring occupying the center of the pore o Chromosome supported by the scaffold. It transport materials in and out of the  It consists of two parallel strands called chromatids, joined to one nucleus another at the centromere, a constricted segment common to both  Thick filaments- radiate out into the cytoplasm and may act as strands. At this site, there is a trilaminar disc, the kinetochore, staging area for the binding of proteins to the transporter of the consisting of two dense layers separated by a paler middle layer. nucleus  The number of chromosomes in somatic cells is specific for the  Nuclear lamina species and is called the genome, the total genetic makeup. In  Nuclear lamina is a continuous meshwork of fine filaments is humans, the genome consists of 46 chromosomes, representing 23 interposed between the inner nuclear membrane and the homologous pairs of chromosomes. One member of each of the peripheral heterochromatin. chromosome pairs is derived from the maternal parent; the other  This nuclear lamina varies in thickness (30-100 nm) in different comes from the paternal parent. Of the 23 pairs, 22 are called cell types, and in the same cell type in different species’ but it autosomes; the remaining pair that determines gender are the sex seems to be a ubiquitous adjunct to the nuclear envelope. chromosomes. The sex chromosomes of the female are two X  Function: Helps to organize and provide support to the lipid bilayer chromosomes (XX) and a male are the X and Y chromosomes (XY). and perinuclear chromatin. o Nucleoplasm  Nucleoplasm, separated from the cytoplasm by the nuclear envelope, is a somewhat viscous substance that surrounds the chromosomes and the nucleoli and is composed of interchromatin and perichromatin granules, water, ribonucleoproteins (RNPs), and the nuclear matrix.  The nuclear matrix is defined in both structural and biochemical terms. Biochemically, the matrix contains about 10% of the total protein, 30% of the RNA, 1% to 3% of the total DNA, and 2% to 5% of the total nuclear phosphate. The structural components include the nuclear pore-nuclear lamina complex, residual nucleoli, residual RNP networks, and fibrillar elements. o Nucleolus  The nucleolus, a dense non-membranous structure located in the nucleus, is observed only during interphase because it dissipates during cell division. It stains basophilic with hematoxylin and eosin, being rich in rRNA and protein.  Usually, there are no more than two or three nucleoli per cell; however, their number, size, and shape are generally species- specific and relate to the synthetic activity of the cell.  Four distinct areas of the nucleolus have been described:  A pale-staining fibrillar center, containing inactive DNA (not being transcribed) o Chromatin pattern and staining  Pars fibrosa, containing nucleolar DNAs being transcribed into  Chromatin is a complex of DNA and proteins and represents the rRNA as well as the protein nucleolin, small nucleolar ribonuclear relaxed, uncoiled chromosomes of the interphase nucleus. It is a proteins, and ribonucleoprotein enzyme fibrillarin, necessary for thread-like structure composed of regularly-spaced discord subunit. the converting of the pre-rRNA into mature rRNA  The thin filaments connecting the nucleosome is a double-stranded  Pars granulosa, in which maturing ribosomal subunits are DNA molecule and have shown that the core of the nucleosome is assembled into the small and large ribosomal subunits an octamer of two molecules each, of 4 histones (H4, H3, H2A, and  Nucleolar matrix, a network of fibers active in nucleolar H2B). A segment of the DNA molecule is coiled around each organization  Chemical composition of the nucleus o It contains nearly all of the deoxyribonucleic acid (DNA) possessed by the cell as well as the mechanisms for ribonucleic acid (RNA) synthesis, and its resident nucleolus is the location for the assembly of ribosomal subunits. Functions of the nucleus o For heredity transmission because of the genes in the DNA o Controls the metabolic processes of the cell CYTOPLASM Cytoplasmic matrix or Cytosol o It is the fluid component of a cell which is mainly made up of water. It  The small subunit has a site for binding mRNA, a P site for contains the structural components of a cell, dissolved proteins, binding peptidyl transfer ribonucleic acid (tRNA), an A site for electrolytes, and glucose. binding aminoacyl tRNAs, and an E site where the tRNA that gave o Parts of the cytosol up its amino acid exits the ribosome. Some of the rRNAs of the  Ectoplasm- peripherally located large subunit are referred to as ribozymes because they have  Endoplasm- internally located containing the organelles enzymatic activity and catalyze peptide bond formation. The small Structural components and large subunits are present in the cytosol individually and do o Organelles not form a ribosome until protein.  Metabolically active structures that perform distinctive functions.  A group or cluster of ribosomes is known as polysome or  Membranous Structures of the Cell polyribosome. These are held together by the messenger RNA.  Most organelles of the cell are covered by membranes composed  Functions primarily of lipids and proteins. These membranes include the cell  Synthesis of new protein molecules in the cell membrane, nuclear membrane, membrane of the endoplasmic  Post-translational modification of these proteins reticulum, and membranes of the mitochondria, lysosomes, and  Manufacture of lipids and integral proteins of cell membrane Golgi apparatus.  Smooth (Agranular) Endoplasmic Reticulum  Non-membranous Structures of the Cell- centriole, ribosomes  Part of the endoplasmic reticulum has no attached ribosomes and  Endoplasmic Reticulum is mainly made up of tubules. This part is called the smooth, or  A network of tubular structures called cisternae and flat vesicular agranular, endoplasmic reticulum. structures in the cytoplasm. This organelle helps process  Functions molecules made by the cell and transports them to their specific  Synthesis of fatty acids and lipid substances and for other destinations inside or outside the cell. The tubules and vesicles processes of the cells promoted by intra-reticular enzymes. interconnect. Also, their walls are constructed of lipid bilayer  In the liver, it plays an important role in the synthesis of lipid membranes that contain large amounts of proteins, similar to the component of very low density lipoproteins (VLDL) that are cell membrane. carriers of cholesterol in the blood.  The space inside the tubules and vesicles is filled with  It is the principal site of detoxification and metabolism of lipid- endoplasmic matrix, a watery medium that is different from fluid soluble exogenous drugs. in the cytosol outside the endoplasmic reticulum. Electron  In muscles, its principal function is the sequestration of calcium micrographs show that the space inside the endoplasmic reticulum that controls muscle contraction. is connected with the space between the two membrane surfaces  Golgi Apparatus of the nuclear membrane.  The Golgi apparatus is composed of one or more series of  Substances formed in some parts of the cell enter the space of the flattened, slightly curved membrane-bounded cisternae (known endoplasmic reticulum and are then directed to other parts of the as faces), the Golgi stack, which resemble a stack of pita breads cell. Also, the vast surface area of this reticulum and the multiple that do not quite contact each other. The periphery of each enzyme systems attached to its membranes provide the cisterna is dilated and is rimmed with vesicles that are in the mechanisms for a major share of the cell’s metabolic functions. process of either fusing with or budding off that particular  Ribosomes and the Rough (Granular) Endoplasmic Reticulum compartment. It is now believed that the flattened shape of the  Attached to the outer surfaces of many parts of the endoplasmic faces of the Golgi apparatus and the budding of vesicles from the reticulum are large numbers of minute granular particles called periphery of the Golgi faces are due to several proteins that are ribosomes. Where these particles are present, the reticulum is associated with the Golgi. called the rough (granular) endoplasmic reticulum. The  Each Golgi stack has three levels of cisternae: ribosomes are composed of a mixture of RNA and proteins; they  The cis-face (and the cis Golgi network) is closest to the RER. function to synthesize new protein molecules in the cell. It is convex in shape and is considered to be the entry face  Each ribosome is composed of a large subunit and a small because newly formed proteins from the RER enter the cis-face subunit, both of which are manufactured or assembled in the before they are permitted to enter the other cisternae of the nucleolus and released as separate entities into the cytosol. Golgi apparatus.  The medial face (intermediate face)  The trans-face (and the trans Golgi network) is concave in shape and is considered to be the exit face because the modified protein is ready to be packaged and to be sent to its destination from here.  Transport of vesicles arriving from the RER fuse with the membranes of the cis-Golgi network (CGN) and release their protein content into its cisterna. Those proteins destined to remain in the RER are returned to the RER along the microtubule- mediated pathway. Small spherical vesicles that bud off the rim of the cis-face of CGN transport the nascent protein to the cis-face of the Golgi stack. From the cis-face, proteins are transported via non-clathrin coated vesicles. Also, protein that form the core of glycoprotein molecules become heavily glycosylated whereas the other proteins acquire or loose sugar moieties.   Cargo that leaves the trans-Golgi network is enclosed in vesicles oxidizing substance and is used in association with catalase, that may do one of the following: another oxidase enzyme present in large quantities in  Insert into the cell membrane as membrane proteins and lipids peroxisomes, to oxidize many substances that might otherwise be  Fuse with the cell membrane such that the protein they carry is poisonous to the cell. For example, about half the alcohol that a immediately released into the extracellular space person drink is detoxified into acetaldehyde by the peroxisomes of  Congregate in the cytoplasm near the apical cell membrane as the liver cells in this manner. secretory granules (vesicles), and, upon a given signal, fuse  Function: To catabolize long-chain fatty acids with the cell membrane for eventual release of the protein  Secretory Vesicles outside of the cell  One of the important functions of many cells is secretion of special  Fuse with late endosomes, releasing their content into that chemical substances. Almost all such secretory substances are organelle, which then becomes a lysosome formed by the endoplasmic reticulum-Golgi apparatus system and  Function: Storage and concentration of secretory products are then released from the Golgi apparatus into the cytoplasm in the form of storage vesicles called secretory vesicles or secretory granules.  Figure 2-6 shows typical secretory vesicles inside pancreatic acinar cells; these vesicles store protein proenzymes (enzymes that are not yet activated). The proenzymes are secreted later through the outer cell membrane into the pancreatic duct and then into the duodenum, where they become activated and perform digestive functions on the food in the intestinal tract.  Centrioles and Centrosome  Centrioles are small, cylindrical, paired structures, arranged perpendicular to each other and are embedded in a matrix of pericentriolar material. The entire complex is known as the centrosome or MTOC and is located in the vicinity of the Golgi  Lysosomes apparatus. The pericentriolar material is composed of the proteins Lysosomes are vesicular organelles that form by breaking off from γ-tubulin and pericentrin, both of which interact with the minus the Golgi apparatus; they then disperse throughout the cytoplasm. ends of the microtubules and anchor them into the centrosome. The lysosomes provide an intracellular digestive system that The centrosome assists in the formation and organization of allows the cell to digest the following: (1) damaged cellular microtubules as well as in its self-duplication before cell division. structures; (2) food particles that have been ingested by the cell;  Centrioles are composed of a specific arrangement of nine triplets and (3) unwanted matter such as bacteria. Lysosome are different of microtubules arranged around a central axis (9 + 0 axoneme in various cell types but are usually 250 to 750 nanometers in pattern). Each microtubule triplet consists of one complete and two diameter. They are surrounded by typical lipid bilayer membranes incomplete microtubules fused to each other, so that the and are filled with large numbers of small granules, 5 to 8 incomplete ones share three protofilaments. The complete nanometers in diameter, which are protein aggregates of as many microtubule “A” is positioned closest to the center of the cylinder; as 40 different hydrolase (digestive) enzymes. “C” is the farthest away.  A hydrolytic enzyme is capable of splitting an organic compound  Functions into two or more parts by combining hydrogen from a water  Association with microtubules- organizing center of the cell molecule with one part of the compound and combining the  During mitotic activity, they are responsible for the formation of hydroxyl portion of the water molecule with the other part of the the spindle apparatus. compound. For example, protein is hydrolyzed to form amino acids,  Give rise to basal bodies that guide the formation of cilia and glycogen is hydrolyzed to form glucose, and lipids are hydrolyzed flagella. to form fatty acids and glycerol.  Mitochondria  Hydrolytic enzymes are highly concentrated in lysosomes.  The mitochondria are called the powerhouses of the cell. Without Ordinarily, the membrane surrounding the lysosome prevents the them, cells would be unable to extract enough energy from the enclosed hydrolytic enzymes from coming into contact with other nutrients, and essentially all cellular functions would cease. substances in the cell and therefore prevents their digestive  The basic structure of the mitochondrion is composed mainly of actions. However, some conditions of the cell break the two lipid bilayer-protein membranes, an outer membrane and an membranes of lysosomes, allowing release of the digestive inner membrane. Many infoldings of the inner membrane form enzymes. These enzymes then split the organic substances with shelves or tubules called cristae onto which oxidative enzymes which they come in contact into small, highly diffusible substances are attached. The cristae provide a large surface area for chemical such as amino acids and glucose. reactions to occur. In addition, the inner cavity of the  Functions mitochondrion, called intercristal space, is filled with a matrix that  Defense of the organism against bacterial invasion by contains large quantities of dissolved enzymes necessary for phagocytosis extracting energy from nutrients. These enzymes operate in  They are involved in the elimination of cell organelles in association with oxidative enzymes on the cristae to cause reorganizations of the cytoplasm associated with changes in oxidation of nutrients, thereby forming carbon dioxide and water physiological activity. This process of controlled degradation of and, at the same time, releasing energy. organelles in a healthy cell is called autophagy to distinguish it  The liberated energy is used to synthesize a high-energy from heterophagy which is the digestion of exogenous material substance called adenosine triphosphate (ATP). ATP is then taken into the cell. transported out of the mitochondrion and diffuses throughout the  Peroxisomes cell to release its own energy wherever it is needed for performing  Peroxisomes are physically similar to lysosomes, but they are cellular functions. different in two important ways. First, they are believed to be  Mitochondria are self-replicative, which means that one formed by self-replication (or perhaps by budding off from the mitochondrion can form a second one, a third one, and so on smooth endoplasmic reticulum) rather than from the Golgi whenever the cell needs increased amounts of ATP. Indeed, the apparatus. Second, they contain oxidases rather than hydrolases. mitochondria contain DNA similar to that found in the cell nucleus. Several of the oxidases are capable of combining oxygen with  Function: Production of energy for the cell hydrogen ions derived from different intracellular chemicals to form hydrogen peroxide (H2O2). Hydrogen peroxide is a highly   The categories of intermediate filaments include:  Keratin- seen in epithelial cells. It stabilizes the shape of the cell and strengthen its attachment to other cells and to the basal lamina  Desmin- seen in muscles. It transmit the pull of contractile proteins and ensure a uniform distribution of tensile force throughout the entire smooth muscle cell  Vimentin- seen in cells derived from mesenchyme and in Inclusions fibroblasts. Because of its intimate association with the nuclear o Inclusions are considered to be nonliving components of the cell that envelope, it may provide the nucleus with mechanical support or do not possess metabolic activity and are not bounded by membranes. maintain its position in the cell The most common inclusions are glycogen, lipid droplets, pigments,  Neurofilament- seen in neurons and provides internal support for and crystals. the nerve cell processes and probably essential for maintaining o Glycogen the gelated state of the cytoplasm  Glycogen is the most common storage form of glucose in animals  Glial filament- found in non-neuronal cells of the CNS and is especially abundant in cells of muscle and liver. It appears in electron micrographs as clusters, or rosettes, of β particles (and larger α particles in the liver) that resemble ribosomes, located in the vicinity of the SER.  On demand, enzymes responsible for glycogenolysis degrade glycogen into individual molecules of glucose. o Lipids  Lipids are triglycerides in storage form and are not only stored in specialized cells (adipocytes) but also are located as individual droplets in various cell types, especially hepatocytes.  Most solvents used in histological preparations extract triglycerides from cells, leaving empty spaces indicative of the locations of lipids. However, with the use of osmium and glutaraldehyde, the lipids (and cholesterol) may be fixed in position as gray-to-black intracellular droplets. Lipids are very efficient forms of energy reserves; twice as many ATPs are derived from 1 g of fat as from 1 g of glycogen. o Pigments  The most common pigment in the body, besides hemoglobin of red o Microtubules blood cells, is melanin, manufactured by melanocytes of skin and  Microtubules are long, straight, rigid, hollow-appearing cylindrical hair, pigment cells of the retina, and specialized nerve cells in the structures which are polarized and have a plus end (β-tubulin) as substantia nigra of the brain. These pigments have protective well as a minus end (α-tubulin), which must be stabilized or it will functions in skin and aid in the sense of sight in the retina, but their depolymerize, thus shortening the microtubule. role in hair and neurons is not understood.  Each microtubule consists of 13 parallel protofilaments composed of  Additionally, in long-lived cells, such as neurons of the central heterodimers of the globular polypeptide α- and β-tubulin subunits, nervous system and cardiac muscle cells, a yellow-to-brown each consisting of about 450 amino acids and each having a pigment, lipofuscin, has been demonstrated. Unlike other molecular mass of about 50,000 Da. inclusions, lipofuscin pigments are membrane-bound and are  Main functions of microtubules believed to represent the indigestible remnants of lysosomal activity.  Provide rigidity and maintain cell shape They are formed from fusion of several residual bodies.  Regulate intracellular movement of organelles and vesicles o Crystals  Establish intracellular compartments  Crystals are not commonly found in cells, with the exception of  Provide the capability of ciliary (and flagellar) motion Sertoli cells (crystals of Charcot-Böttcher), interstitial cells  Microtubule-associated Proteins (crystals of Reinke) of the testes, and, occasionally, in  Dynein- in the presence of ATP, dynein moves the vesicle toward macrophages. It is believed that these structures are crystalline the minus end of the microtubule (toward the MTOC) forms of certain proteins.  Kinesin- effects vesicular (and organelle) transport toward the Cytoskeletal components plus end (away from the MTOC) o The cytoplasm of animal cells contains a cytoskeleton, an intricate  Axonemal dynein- serves as motor for ciliary movement three-dimensional meshwork of protein filaments that are responsible  Dynamin- forms a regularly-spaced cross-bridge between for the maintenance of cellular morphology. Additionally, the neighboring microtubules and serve as the motor for sliding of cytoskeleton is an active participant in cellular motion, whether of some microtubules of the bundle with respect to others, resulting organelles or vesicles within the cytoplasm, regions of the cell, or the to elongation of bundles entire cell. o Thin filaments- actin and myosin CELL MEMBRANE o Intermediate filaments Chemo-structural characteristics of the cell membrane  Their size is between thick and thin filaments and are consequently o The cell membrane (also called the plasma membrane) envelops the named intermediate filaments. These filaments and their cell and is a thin, pliable, elastic structure only 7.5 to 10 nanometers associated proteins accomplish the following: thick. It is composed almost entirely of proteins and lipids. The  Provide structural support for the cell approximate composition is 55% proteins, 25% phospholipids, 13%  Form a deformable three-dimensional structural framework for the cholesterol, 4% other lipids, and 3% carbohydrates. cell o The Cell Membrane Lipid Barrier Impedes Penetration by Water-  Anchor the nucleus in place Soluble Substances.  Provide an adaptable connection between the cell membrane and  Figure 2-3 shows the structure of the cell membrane. Its basic the cytoskeleton structure is a lipid bilayer, which is a thin, double-layered film of  Furnish a structural framework for the maintenance of the nuclear lipids- each layer only one molecule thick- that is continuous over envelope as well as its reorganization subsequent to mitosis the entire cell surface. Interspersed in this lipid film are large globular proteins.   The basic lipid bilayer is composed of three main types of lipids-  There is also inside-outside asymmetry of the phospholipids. phospholipids, sphingolipids, and cholesterol. Phospholipids are The choline-containing phospholipids (phosphatidylcholine and the most abundant cell membrane lipids. One end of each sphingomyelin) are located mainly in the outer leaflet; the phospholipid molecule is hydrophilic and soluble in water. The aminophospholipids (phosphatidylserine and other end is hydrophobic and soluble only in fats. The phosphate phosphatidylethanolamine) are preferentially located in the inner end of the phospholipid is hydrophilic, and the fatty acid portion is leaflet. Obviously, if this lipid asymmetry is to exist at all, there must hydrophobic. be limited transverse mobility, or “flip-flop” the membrane  Because the hydrophobic portions of the phospholipid molecules are phospholipids. In fact, phospholipids in synthetic bilayers exhibit an repelled by water but are mutually attracted to one another, they extraordinarily slow rate of flip-flop; the half-life of the asymmetry in have a natural tendency to attach to one another in the middle of the these synthetic bilayers is on the order of several weeks. membrane, as shown in Figure 2-3. The hydrophilic phosphate  The mechanisms involved in the lipid asymmetry are not well portions then constitute the two surfaces of the complete cell understood. The enzymes involved in the synthesis of phospholipids membrane, in contact with intracellular water on the inside of the are located on the cytoplasmic side of microsomal membrane membrane and extracellular water on the outside surface. vesicles. Translocases (flippases) exist that transfer certain  The lipid layer in the middle of the membrane is impermeable to the phospholipids (e.g., phosphatidylcholine) from the inner to the outer usual water-soluble substances, such as ions, glucose, and urea. leaflet. Specific proteins that preferentially bind individual Conversely, fat-soluble substances, such as oxygen, carbon dioxide, phospholipids also appear to be present in the two leaflets; thus, lipid and alcohol, can penetrate this portion of the membrane with ease. binding also contributes to the asymmetric distribution of specific  Sphingolipids, derived from the amino alcohol sphingosine, also lipid molecules. In addition, phospholipid exchange proteins have hydrophobic and hydrophilic groups and are present in small recognize certain phospholipids and transfer them from one amounts in the cell membranes, especially nerve cells. Complex membrane (e.g., the ER) to others (e.g., mitochondrial and sphingolipids in cell membranes are thought to serve several peroxisomal). A related issue is how lipids enter membranes. This functions, including protection from harmful environmental factors, has not been studied as intensively as the topic of how proteins enter signal transmission, and adhesion sites for extracellular proteins. membranes and knowledge is still relatively meager.  Cholesterol molecules in membranes are also lipids because their  Many membrane lipids are synthesized in the ER. At least 3 steroid nuclei are highly fat-soluble. These molecules, in a sense, pathways have been recognized: (1) transport from the ER in are dissolved in the bilayer of the membrane. They mainly help vesicles, which then transfer the contained lipids to the recipient determine the degree of permeability (or impermeability) of the membrane; (2) entry via direct contact of one membrane (e.g., the bilayer to water-soluble constituents of body fluids. Cholesterol ER) with another, facilitated by specific proteins; and (3) transport controls much of the fluidity of the membrane as well. via the phospholipid exchange proteins (also known as lipid transfer proteins) mentioned earlier, which only exchanges lipids, but does not cause net transfer.  There is further asymmetry with regard to GSLs and glycoproteins; the sugar moieties of these molecules all protrude outward from the plasma membrane and are absent from its inner face. o Membranes contain integral and peripheral proteins  It is useful to classify membrane proteins into two types: integral and peripheral.  Most membrane proteins fall into the integral class, meaning that they interact extensively with the phospholipids and require the use Chemical compositions of detergents for their solubilization. Also, they generally span the o Membrane lipids are amphipathic bilayer as a bundle of α-helical transmembrane segments. Integral  All major lipids in membranes contain both hydrophobic and proteins are usually globular and are themselves amphipathic. They hydrophilic regions and are therefore termed amphipathic. If the consist of two hydrophilic ends separated by an intervening hydrophobic region were separated from the rest of the molecule, it hydrophobic region that traverses the hydrophobic core of the would be insoluble in water but soluble in organic solvents. bilayer. Conversely, if the hydrophilic region were separated from the rest of  As the structures of integral membrane proteins were being the molecule, it would be insoluble inorganic solvents but soluble in elucidated, it became apparent that certain ones (e.g., transporter water. The amphipathic nature of a phospholipid is represented in molecules, ion channels, various receptors, and G proteins) span Figure 40–3. Thus, the polar head groups of the phospholipids and the bilayer many times, whereas other simple membrane proteins the hydroxyl group of cholesterol interface with the aqueous (e.g., glycophorin A) span the membrane only once. Integral environment; a similar situation applies to the sugar moieties of the proteins are asymmetrically distributed across the membrane GSLs. bilayer. This asymmetric orientation is conferred at the time of their  Saturated fatty acids form relatively straight tails, whereas insertion in the lipid bilayer during biosynthesis in the ER. unsaturated fatty acids, which generally exist in the cis form in  Peripheral proteins do not interact directly with the hydrophobic membranes, form “kinked” tails (see Figure 40-3). As the number of cores of the phospholipids in the bilayer and thus do not require use double bonds within the lipid side chains increase, the number of of detergents for their release. They are bound to the hydrophilic kinks in the tails increases. As a consequence, the membrane lipids regions of specific integral proteins and head groups of become less tightly packed and the membrane more fluid. phospholipids and can be released from them by treatment with salt o Membranes are asymmetric structures solutions of high ionic strength.  Proteins have unique orientations in membranes, making the  For example, ankyrin, a peripheral protein, is bound to the inner outside surfaces different from the inside surfaces. An inside- aspect of the integral protein “band 3” of the erythrocyte outside asymmetry is also provided by the external location of the membrane. Spectrin, a cytoskeletal structure within the carbohydrates attached to membrane proteins. In addition, specific erythrocyte, is in turn bound to ankyrin and thereby plays an proteins are located exclusively on the outsides or insides of important role in maintenance of the biconcave shape of the membranes. erythrocyte.  There are also regional heterogeneities in membranes. Some,  Functions of the protein components such as occur at the villous borders of mucosal cells, are almost  Integral Proteins macroscopically visible. Others, such as those at gap junctions, tight  Provides channels or pores through which water molecules and junctions, and synapses, occupy much smaller regions of the water-soluble substances can diffuse between the extracellular membrane and generate correspondingly smaller local asymmetries. and intracellular fluids.   Acts as a carrier protein for transporting substances that cannot o The concept of fluidity penetrate the lipid layer.  The model is often likened to integral membrane protein “icebergs”  Peripheral Proteins floating in a sea of (predominantly) fluid phospholipid molecules.  Functions almost entirely as enzymes or other types of Early evidence for the model was the finding that well characterized, controllers of intracellular function. fluorescently labeled integral membrane proteins could be seen microscopically to rapidly and randomly redistribute within the plasma membrane of a hybrid cell formed by the artificial fusion of two different (mouse and human) parent cells (one labeled the other not). It has subsequently been demonstrated that phospholipids undergo even more rapid lateral diffusion with subsequent redistribution within the plane of the membrane. Measurements indicate that within the plane of the membrane, one molecule of phospholipid can move several micrometers per second.  The features that favor fluidity  The phase changes- and thus the fluidity of membranes- are largely dependent on the lipid composition of the membrane. In a lipid bilayer, the hydrophobic chains of the fatty acids can be highly aligned or ordered to provide a rather stiff structure. As the temperature increases, the hydrophobic side chains undergo a transition from the ordered state (more gel-like or crystalline phase) to a disordered one, taking on a more liquid-like or fluid arrangement. o Membrane Carbohydrates- The Cell “Glycocalyx.”  The temperature at which membrane structure undergoes the  Membrane carbohydrates occur almost invariably in combination transition from ordered to disordered (i.e., melts) is called the with proteins or lipids in the form of glycoproteins or glycolipids. “transition temperature” (Tm). Longer and more saturated fatty In fact, most of the integral proteins are glycoproteins, and about acid chains interact more strongly with each other via their one-tenth of the membrane lipid molecules are glycolipids. The extended hydrocarbon chains and thus cause higher values of Tm- glyco- portions of these molecules almost invariably protrude to the that is, higher temperatures are required to increase the fluidity of outside of the cell, dangling outward from the cell surface. Many the bilayer. On the other hand, unsaturated bonds that exist in other carbohydrate compounds, called proteoglycans- which are the cis configuration tend to increase the fluidity of a bilayer by mainly carbohydrates bound to small protein cores- are loosely decreasing compactness of the side chain packing without attached to the outer surface of the cell as well. diminishing hydrophobicity. The phospholipids of cellular  Thus, the entire outside surface of the cell often has a loose membranes generally contain at least one unsaturated fatty acid carbohydrate coat called the glycocalyx. The carbohydrate with at least one cis double bond. moieties attached to the outer surface of the cell have several  The importance of fluidity important functions:  The fluidity of a membrane significantly affects its functions. As  Many of them have a negative electrical charge, which gives most membrane fluidity increases, so does its permeability to water and cells an overall negative surface charge that repels other other small hydrophilic molecules. The lateral mobility of integral negatively charged objects. proteins increases as the fluidity of the membrane increases. If the  The glycocalyx of some cells attaches to the glycocalyx of other active site of an integral protein involved in a given function is cells, thus attaching cells to one another. exclusively in its hydrophilic regions, changing lipid fluidity will  Many of the carbohydrates act as receptors for binding hormones, probably have little effect on the activity of the protein; however, if such as insulin. When bound, this combination activates attached the protein is involved in a transport function in which transport internal proteins that in turn activate a cascade of intracellular components span the membrane, lipid-phase effects may enzymes. significantly alter transport rate.  Some carbohydrate moieties enter into immune reactions.  The insulin receptor is an excellent example of altered function  The most important function of the glycocalyx is protection of the cell with changes in fluidity. As the concentration of unsaturated fatty from interaction with inappropriate proteins from chemical and acids in the membrane is increased (by growing cultured cells in a physical injuries. medium rich in such molecules), fluidity increases. Increased Molecular properties of the cell membrane fluidity alters the receptor such that it binds insulin more effectively. o It has a mosaic model At normal body temperature (37°C), the lipid bilayer is in a fluid o It is fluid state. Underscoring the importance of membrane fluidity, it has o Composed of lipids, proteins, and carbohydrates been shown that bacteria can modify the composition of their membrane lipids to adapt to changes in temperature.  The importance of cholesterol in modulating fluidity  Cholesterol acts as a buffer to modify the fluidity of membranes. At temperatures below the Tm, it interferes with the interaction of the hydrocarbon tails of fatty acids and thus increases fluidity. At temperatures above the Tm, it limits disorder because it is more rigid than the hydrocarbon tails of the fatty acids and cannot move in the membrane to the same extent, thus limiting, or “buffering” o The mosaic fluid model membrane fluidity.  The mosaic model of membrane structure means the membrane Antigenicity of the cell membrane consists of a bimolecular lipid layer with proteins inserted in it or o The antigenicity of the cell membrane is due to the presence of bound to either surface. Integral membrane proteins are firmly antigens on its surface. embedded in the lipid layers. Some of these proteins completely Selective permeability of the cell membrane span the bilayer and are called transmembrane proteins, while o Selective Permeability of Protein Channels. Many protein channels others are embedded in either the outer or inner leaflet of the lipid are highly selective for transport of one or more specific ions or bilayer. Loosely bound to the outer or inner surface of the membrane molecules. This selectivity results from specific characteristics of the are peripheral proteins. Many of the proteins and all the glycolipids channel, such as its diameter, shape, and the nature of the electrical have externally exposed oligosaccharide carbohydrate chains. charges and chemical bonds along its inside surfaces.  o Potassium channels permit passage of potassium ions across the CASE 2 cell membrane about 1000 times more readily than they permit TYPES OF TRANSPORT OF SUBSTANCES passage of sodium ions. This high degree of selectivity cannot be The fluid inside the cells (ICF) is very different from the fluid which explained entirely by the molecular diameters of the ions because circulates freely around and outside the cells (ECF). Their chemical potassium ions are slightly larger than sodium ions. Using x-ray compositions also vary. ICF has large quantities of potassium, crystallography, potassium channels were found to have a tetrameric magnesium, and phosphate ions, while the ECF has more of sodium, structure consisting of 4 identical protein subunits surrounding a chlorides, and bicarbonate ions. These differences leads to the transport central pore. At the top of the channel pore are pore loops that form of substances across the cell membrane. a narrow selectivity filter. Lining the selectivity filter are carbonyl Passive transport or Diffusion oxygens. When hydrated potassium ions enter the selectivity filter, o Diffusion means the random free movement of substance molecule by they interact with the carbonyl oxygens and shed most of their bound molecule caused by the normal kinetic motion of matter, either through water molecules, permitting the dehydrated potassium ions to pass the molecular spaces in the membrane or in combination with carrier through the channel. The carbonyl oxygens are too far apart, however, proteins. This movement of particles is called heat- the greater the to enable them to interact closely with the smaller sodium ions, which motion, the higher is the temperature. The motion never ceases under are therefore effectively excluded by the selectivity filter from passing any condition except at absolute zero temperature. through the pore. o When a moving particle A approaches a stationary molecule B, the o Different selectivity filters for the various ion channels are believed to electrostatic forces of molecule A repel molecule B, thus momentarily determine, in large part, the specificity of various channels for cations adding some energy of motion to molecule B. Consequently, molecule or anions or for particular ions, such as sodium (Na+), potassium (K+), B gains kinetic energy of motion, while molecule A slows down, losing and calcium (Ca2+), that gain access to the channels. some of its kinetic energy. Thus, a single molecule bounces among o One of the most important of the protein channels, the sodium the other molecules- first on one direction, then another, then another, channel, is only 0.3 to 0.5 nanometer in diameter, but the ability of etc. bouncing randomly hundreds or even thousands of times or sodium channels to discriminate sodium ions among other competing millions of times per second. This continual movement of molecules ions in the surrounding fluids is crucial for proper cellular function. The among each other in liquids or in gases is called diffusion. narrowest part of the sodium channel’s open pore, the selectivity Simple diffusion filter, is lined with strongly negatively charged amino acid residues, o It is a passive process by which uncharged particles in solution flow as shown in the top panel of Figure 4-5. These strong negative down their concentration (chemical) gradient (i.e., particles move from charges can pull small dehydrated sodium ions away from their areas of high concentration to areas of lower concentration). hydrating water molecules into these channels, although the ions do o This is through the cell membrane which is essentially a sheet of lipid not need to be fully dehydrated to pass through the channels. Once in material, called the lipid matrix which may be covered partially on the channel, the sodium ions diffuse in either direction according to the each surface by a thin layer of protein. The fluids on each side of the usual laws of diffusion. Thus, the sodium channel is highly selective membrane are believed to penetrate the protein portions of the for passage of sodium ions. membrane with ease, but the lipid portion of the membrane behaves Electrical properties of the cell membrane like a different fluid medium, acting as a limiting boundary between the o This is due to the presence of channels in the membrane such as ion ECF and ICF. Thus, there are two different methods by which and voltage-gated channels. This can be also attributed to the substances can diffuse through the membranes: presence of the cell coat which confers electrostatic change on its cell  By becoming dissolved in the lipid and diffusing though it in the same surface and promotes adhesion among cells. way that diffusion occurs in water. Substances which are soluble in Functions of the cell membrane the lipid of the cell membrane, as well as in water are: oxygen, o Maintaining the structural integrity of the cell carbon dioxide, alcohol, fatty acids, and a few less important o Controlling movements of substance in and out of the cell (selective substances. When one of these come in contact with the membrane, permeability) it immediately becomes dissolved in the lipid and continues to o Regulation of cell to cell interactions diffuse in exactly the same manner within the water medium on o Recognition via receptors: antigens, foreign cells, as well as altered either side of the membrane. The molecule will continue to move cells randomly within the substance of the membrane following the same o Acting as an interface between the cytoplasm and the external milieu pattern of undergoing random motion in the surrounding fluids. o Establishing transport systems for specific molecules  The primary factor that determined how rapidly a substance can o Transducing extracellular, physical, and/or chemical signals into diffuse through the lipid matrix of the cell membrane is its solubility intracellular events in lipids. If it is very soluble, it becomes dissolved in the membrane very easily, and therefore passes on through.  In fact, if its solubility in lipids is greater, it will actually diffuse even more rapidly through the membrane than in the water of the surrounding fluids; however, a substance that dissolves poorly in lipids will be greatly retarded (e.g., oxygen, which is very soluble, passes through the lipid matrix many times as rapidly as through water, while water itself, which is almost completely insoluble in lipids, passes through the membrane lipid matrix almost not at all)  By diffusing through minute pores that pass directly through the membrane at wide intervals over the surface; these pores are probably created by protein molecules that penetrate all the way IN-VIVO AND IN-VITRO REACTION through the membrane. Water and many of the dissolved ions seem to go through the membrane pores. In vitro- an experiment taking place outside of a living body (e.g., in a o Process. No external source of energy (or driving force) is tissue culture dish). required to move particles down a concentration gradient by diffusion. In vivo- occurring in a living body, used in experimental situations to Simple diffusion occurs because the heat content of the solution keeps describe events taking place in real life. all of the solvent and solute particles of the solution in constant motion.  Each particle moves in an unpredictable (random) fashion; however, it is more likely that a particle will move from an area of high concentration to an area of lower concentration.  Net movement ceases when the concentration of the particles is equal everywhere within the solution (diffusional equilibrium).   Although random movement of the particles continues after pores. Each positive charge causes a sphere of electrostatic diffusional equilibrium is achieved, the concentration of the particles space charge to protrude into the lumen of the pore. throughout the solution remains the same.  A positive ion attempting to pass through a pore also exerts a  Kinetics of diffusion: The concentration difference sphere of positive electrostatic charge so that the two positive  If a large amount of a dissolved substance is placed in a solvent charges repel each other. This repulsion, therefore, blocks or at one end of chamber, it immediately begins to diffuse toward the greatly impedes movement of the positive ion through the pore. opposite end of the chamber. If the same amount of substance is In contrast, negative ions pass through mammalian membrane placed in the opposite end of the chamber, it will also begin to more easily thus, chloride and other negative ions permeates diffuse to the first end; thus, the same amount of substance will the cell membrane about two times as easily as potassium ions, tend to diffuse towards each other, as a result the net rate of and 100 to 200 times as easily as sodium ions. This is believed diffusion from one end to the other is zero. to be due to the absence of negative charges lining the pores.  If, however, the concentration of the substance is greater at one  Excess calcium in the ECF causes the permeability to decrease, end of the chamber than at the other end, the net rate of diffusion while diminished calcium causes a considerable increase in from the area of high concentration to low concentration is directly permeability. This factor is especially important in nerve since the proportional to the larger concentration minus the lower enlarged pores that occur in ECF calcium deficiency cause concentration. excessive diffusion of ions, which will result in spurious discharge  The total concentration change along the axis of the chamber of nervous impulses throughout the body. called concentration difference, and the concentration  The antidiuretic hormone secreted by the hypothalamus has an difference divided by the distance is called the concentration or important effect on the cells lining the collecting ducts of the diffusion gradient. kidneys. Increased quantities of hormone increase the pore o Rate. Fick’s law of diffusion describes the rate at which a material diameter which allows water and other substances to diffuse out diffuses through a membrane as a function of its concentration of the tubules and back into the blood with ease - thus diminishing gradient. It has two forms: the amount of urine excreted or formed.  Factors That Affect Net Rate of Diffusion , where:  By now, it is evident that many substances can diffuse through the Flux = the amount of material (mmol) moved per unit time cell membrane. What is usually important is the net rate of D = the diffusion coefficient (cm2/sec) diffusion of a substance in the desired direction. This net rate is A = the area of the membrane (cm2) determined by several factors. d = the diffusion distance, or the thickness of the membrane (cm)  Net Diffusion Rate Is Proportional to the Concentration Cin and Cout = the concentrations of the material on the inside and Difference Across a Membrane. outside of the membrane, respectively (mmol/L or mmol/1000cm3)  In a cell membrane with a high concentration of a substance on  The negative sign indicates that the material is moving down its the outside and a low concentration of a substance on the inside. concentration gradient. The rate at which the substance diffuses inward is proportional  Fick’s law can be simplified when biologic membranes are to the concentration of molecules on the outside because this considered, because the thickness of the membrane always is concentration determines how many molecules strike the approximately 10-6 cm. Dividing the diffusion coefficient (D) by 10-6 outside of the membrane each second. (x) yields the permeability coefficient of the membrane, and the  Conversely, the rate at which molecules diffuse outward is Fick’s law becomes: proportional to their concentration inside the membrane. Therefore, the rate of net diffusion into the cell is proportional to  Where P is the permeability coefficient (cm/sec) the concentration on the outside minus the concentration on the o Permeability. The permeability coefficient (and the diffusion inside: coefficient) depend on the solute and the membrane through which diffusion is taking place. in which Co is the concentration outside and Ci is the  Lipid-soluble particles diffuse through the lipid bilayer of the cell concentration inside the cell. membrane. Thus, their permeability is proportional to their lipid  If the same amount of substance is placed outside and inside solubility. the cell, it will begin to diffuse first towards one side; thus, the  Water-soluble particles diffuse through the aqueous channels same amount of substance will diffuse each other, as a result formed by transmembrane proteins. Thus, their permeability is the net rate of diffusion from one end to the other is zero. proportional to their molecular size, shape, and change.  Membrane Electrical Potential and Diffusion of Ions- The  Factors that affect permeability “Nernst Potential”  Effect of Pore Size on Diffusion Through the Pore  If an electrical potential is applied across the membrane, as Permeability shown in Figure 4-9B, the electrical charges of the ions cause  Permeability can be defined as the rate of transport through the them to move through the membrane even though no membrane for a given concentration difference. All substances concentration difference exists to cause movement. having a size generally smaller than the pore diameter, i.e.,  Thus, in the left panel of Figure 4-9B, the concentration of water, urea molecules, and chloride ions, pass through the pore negative ions is the same on both sides of the membrane, but with great ease. Thus, the rate per second of diffusion of water, a positive charge has been applied to the right side of the for instance, in each direction through the pores of the cell is membrane, and a negative charge has been applied to the left, about one hundred times as great as the volume of the cell itself. creating an electrical gradient across the membrane. The  It is fortunate that an equal amount of water diffuses out of the positive charge attracts the negative ions, whereas the negative cell, equalizing those that diffuses in, which keeps the cell from charge repels them. Therefore, net diffusion occurs from left to either swelling or shrinking, despite the rapid rate of diffusion. right. Any substance, i.e., glucose molecules, whose diameter is much  After some time, large quantities of negative ions have moved bigger than the pore size will have extreme difficulty, if ever they to the right, creating the condition shown in the right panel of pass, passing through the pores. Figure 4-9B, in which a concentration difference of the ions has  Effect of Electrical Charge on Transport of lons Through the developed in the direction opposite to the electrical potential Membrane difference. The concentration difference now tends to move the  Positively charged particles, such as Na+ and K+ ions pass ions to the left, whereas the electrical difference tends to move through the cell membrane with extreme difficulty. This is them to the right. When the concentration difference rises high believed to be due to the presence of positive charges of enough, the two effects balance each other. At normal body proteins or of absorbed positive ions, i.e., calcium lining the temperature (98.6°F; 37°C), the electrical difference that will  balance a given concentration difference of univalent ions- concentrations on the two sides, no net Na+ diffusion occurs. Only such as Na+ ions- can be determined from the following formula, Cl- diffuses down its concentration gradient from right to left. called the Nernst equation:  With the movement of only a few thousand Cl- ions per square micron of membrane (a change too small to be measurable by available techniques), a substantial membrane voltage develops, left in which EMF is the electromotive force (voltage) between side side negative. This voltage now has two effects: (1) it begins to drive 1 and side 2 of the membrane, C1 is the concentration on side Na+ ions across the membrane from right to left (Fig. 2.15B), and (2) 1, and C2 is the concentration on side 2. The polarity of the it opposes further Cl- movement from right to left. Ultimately, an voltage on side 1 in the equation above is + for the negative ions equilibrium is reached between oppositely-directed chemical and – for the positive ions. This equation is extremely important gradients for Na+ and Cl- and the membrane voltage (Fig. 2.15C). in understanding the transmission of nerve impulses. Again, within the limits of detection, electroneutrality will be maintained within each compartment (concentration of anions equals concentration of cations). In the Donnan equilibrium, Na+ and Cl- conductance are present, and no energy is put in. Facilitated diffusion (Carrier-mediated diffusion) o It is a carrier-mediated process that enables particles that are too large to flow through membrane channels by simple diffusion (e.g., many ions and nutrients) to pass through the membrane. For example, facilitated diffusion accomplishes the transport of glucose into RBCs and muscle and into adipose tissue (when insulin is pr