Cell Physiology PDF

hPhY 201: cell PhYsiologY AUGUSTINE BANLIBO DUBO ([email protected]) (ROOM 112) Department of Human physiology, Faculty of Basic Medical Sciences, Ahmadu Bello University, Zaria - Nigeria 1  reFerence teXt...

hPhY 201: cell PhYsiologY AUGUSTINE BANLIBO DUBO ([email protected]) (ROOM 112) Department of Human physiology, Faculty of Basic Medical Sciences, Ahmadu Bello University, Zaria - Nigeria 1  reFerence teXt booKs 1. rhoADes & bell MeDicAl PhYsiologY 2. VAnDer et Al hUMAn PhYsiologY 3. sherWooD’s FUnDAMentAl oF hUMAn PhYsiologY 4. linDA s. costAnZo : PhYsiologY 5. stUArt irA: hUMAn PhYsiologY 6. gUYton & hAll: teXtbooK oF MeDicAl PhYsiologY 7. gAnong’s reVieW oF MeDicAl PhYsiologY 2  contents Introduction to Physiology and concept of Homeostasis Composite cell, Cell theory and physiology of cell membrane Intracellular organelles and functions Structure and functions of DNA and RNA Intercellular connections and communications Transport across cell membrane Establishment of resting membrane potential (RMP) 3  INTRODUCTION The Greek philosopher, Erasistratus (304–250 B.C.)  Is considered the father of physiology because he attempted to apply physical laws to the study of human function. Galen (A.D. 130–201) wrote widely on the subject of physiology and was considered the supreme authority until the advent of the Renaissance. 4 William Harvey (1578–1657) demonstrated that the heart pumps blood through a closed system of vessels. However, the father of modern physiology is the French physiologist Claude Bernard (1813–1878) He He observed that the milieu interieur (“internal environment”) remains remarkably constant despite changing conditions in the external environment. The American physiologist Walter B. Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. 5 Physiology (from the Greek physis = nature; logos = study)  is the study of biological function of how the body works, from cell to tissue, organ, system, and of how the organism as a whole accomplishes particular tasks essential for life. Human Physiology is a science that attempts to explain the specific characteristics and mechanisms of the human body that make it a living being. is the study of the integrated normal function of the human body. 6 For a person to remain healthy, physiologic conditions in the body must be optimal and closely regulated. Regulation requires efficient communication between cells and tissues. Cells that have similar functions are grouped into categories called tissues. The entire body is composed of only four major types of tissues, which are grouped into anatomical and functional units called organs. Organs, in turn, may be grouped together by common functions into systems. The systems of the body act in a coordinated fashion to maintain the entire organism. 7 In the study of physiology, the emphasis is on mechanisms with a question that begins with the word ‘how’ Answers usually involves cause­and­effect sequences which are derived empirically from experimental evidences. A related science, pathophysiology (physiology gone wrong) is concerned with how physiological processes are altered in disease or injury.  Pathophysiology and the study of normal physiology complement one another 8  THE CONCEPT OF HOMEOSTASIS The fluid collectively contained within all body cells is called intracellular fluid (ICF) while the fluid outside the cells is called extracellular fluid (ECF). ECF is made up of two components: the plasma, the fluid portion of the blood, and the interstitial fluid, which surrounds and bathes the cells There is transfer of materials between the external environment and the internal environment so that the composition of the internal environment is appropriately maintained to support the life and functioning of the cells 9 Claude Bernard was the first to formulate the concept of the internal environment (milieu intérieur). He pointed out that an external environment surrounds multicellular organisms (air or water).  And a liquid internal environment (extracellular fluid) surrounds the cells that make up the organism. For optimal cell, tissue, and organ function in animals, several facets of the internal environment must be maintained within narrow limits. These include oxygen and carbon dioxide tensions; conc of glucose and other nutrients; volume and pressure; conc of water salts and other electrolytes (ions); pH and temperature 10 Walter B. Cannon explained the body’s capacity for self­regulation by defining the term homeostasis as the maintenance of steady states in the body by coordinated physiologic mechanisms.  The body must sense departures from normal and then be able to activate mechanisms for restoring physiologic conditions to normal. Deviations from normal conditions may vary between too high and too low, so mechanisms exist for opposing changes in either direction. Eg glucose level 11 Homeostatic regulation of a physiologic variable often involves several cooperating mechanisms activated at the same time or in succession When the body is unable to restore physiologic variables, then disease or death can result. The ability to maintain homeostatic mechanisms varies over a person’s lifetime. Some homeostatic mechanisms not being fully developed at birth and others declining with age 12 13 The Body Systems Contributions to Homeostasis 14  HOMEOSTATIC CONTROL SYSTEM A homeostatic control system is a functionally interconnected network of body components that operate to maintain a given factor in the internal environment relatively constant around an optimal level. To maintain stable or constant internal environment, the control system must be able to: Detect deviations from normal in the internal environmental factor that needs to be held within narrow limits  Integrate this information with any other relevant information Make appropriate adjustments in the activity of the body parts responsible for restoring this factor to its desired value 15 In order for internal constancy to be maintained:  Changes in the regulated variable in the body must stimulate sensors (detectors, receptors), That can send information to an integrating center (integrator or comparator). This allows the integrating center to detect changes from a set point via the responses of effectors (muscles or glands) 16 17 The integrating center may cause increases or decreases in effector action to counter the deviations from the set point and defend homeostasis This is achieved through feedback signal which is divided into two: Negative feedback Positive feedback. 18  Negative Feedback Mechanism A change in a homeostatically controlled factor restore the factor to normal by moving the factor in the opposite direction of its initial change. That is, a corrective adjustment opposes the original deviation from the normal desired level. With negative feedback, a regulated variable is sensed, information is fed back to the controller, and the effector acts to oppose change (hence, the term negative). 19 For example, if the body temperature exceeds the set point of 37°C.  Sensors in a part of the brain detect this deviation and send signal to the integrating center (also in the brain), The center then stimulates activities of effectors (including sweat glands) that lower the temperature. Another example, if the blood glucose concentration falls below normal. The effectors act to increase the blood glucose. 20 21 22 The maintenance of water and salts in the body is referred to as osmoregulation or fluid balance. Loss of water results in an increased concentration of salts in the blood and tissue fluids, which is sensed by the cells in the brain.  The brain responds by telling the kidneys to reduce secretion of water and also by increasing the sensation of being thirsty.  Together the reduction in water loss in the kidneys and increased water intake return the blood and tissue fluids to the correct osmotic concentration 23  Positive Feedback Mechanism With positive feedback, a variable is sensed and action is taken to reinforce a change in the variable. The term positive refers to the response being in the same direction, leading to a cumulative or amplified effect. Positive feedback does not lead to stability or regulation, but to the opposite a progressive change in one direction. Because the major goal in the body is to maintain stable, homeostatic conditions, positive feedback does not occur nearly as often as negative feedback. 24 One example of positive feedback in a physiologic process is the sensation of needing to urinate.  As the bladder fills, mechanosensors in the bladder are stimulated and the smooth muscle in the bladder wall begins to contract. As the bladder continues to fill and become more distended, the contractions increase and the need to urinate become more urgent. Another example of positive feedback occurs during the follicular phase of the menstrual cycle. The female sex hormone estrogen stimulates the release of luteinizing hormone, which in turn causes further estrogen synthesis by the ovaries. This positive feedback culminates in ovulation. 25 Positive feedback, if unchecked, can lead to a vicious cycle and dangerous situations. For example, a heart may be so weakened by disease that it cannot provide adequate blood flow to the muscle tissue of the heart. This leads to a further reduction in cardiac pumping ability, even less coronary blood flow, and further deterioration of cardiac function. 26 In some instances, the body uses positive feedback to its advantage. Blood clotting is an example; when a blood vessel is ruptured and a clot begins to form, multiple enzymes called clotting factors are activated within the clot. Some of these enzymes act on other unactivated enzymes of the immediately adjacent blood, thus causing more blood clotting. This process continues until the hole in the vessel is plugged and bleeding no longer occurs. 27 Childbirth is another instance in which positive feedback is valuable. When uterine contractions become strong enough Stretching of the cervix sends signals through the uterine muscle back to the body of the uterus, causing even more powerful contractions. When this process becomes powerful enough, the baby is born. If it is not powerful enough, the contractions usually die out and a few days pass before they begin again. 28 29  CELL The word cell was first used by Robert Hooke (1665) He described small chambers within cork under a microscope to resembled “honey- comb,” or “small boxes or bladders of air.” which he called cells 30 Mathias Schleiden (1839) and Theodore Schwann (1830) laid the foundation for the idea that cells are the fundamental components of plants and animals. Rudolf Virchow (1855), published an editorial essay “Cellular Pathology” with the phrase omnis cellula e cellula (L) It is translated ‘‘all cells arise from cells’’ which popularized the concept of cell theory 31  Cell Theory The cell is the basic functional and structural unit of all living organisms. All living organisms are made up of cells. All cells arise from pre­existing cells. Viruses??? The female egg (Ovum) is the largest cell in the human body. The smallest cell, however, is the sperm. 32 33 34 A cell is the simplest structural units into which a complex multicellular organism can be divided and still retain the functions characteristic of life. Organisms made up of a single cell are ‘unicellular’ whereas organisms made up of many cells are ‘multicellular In unicellular organisms, all vital processes occur in a single cell. Whereas in multicellular organisms various cell groups organized into tissues and organs to perform functions. 35  Characteristics of Cells Certain fundamental activities are common to almost all cells and represent the minimal requirements for maintaining cell integrity and life. Cells contain hereditary information (DNA) which is passed on from cell to cell (Except erythrocyte) Cells require nutrition and oxygen Energy flow (metabolisms) occur within cells which is necessary for activities 36 Cells remove metabolic waste products such as CO2 Cells respond to the entry of pathogenic organisms and toxic substances Cells reproduce by division i.e they contain all the information required for replicating themselves (Except nerve cells). Thus, is even possible to reproduce the entire organism from almost any single cell of the organism. The activity of an organism depends on the total activities of independent cells All cells have the same basic chemical compositions 37 38 Human cells are divided into three principal parts: Plasma (cell) membrane: It surrounds the cell, gives it form, and separates the cell’s internal structures from the extracellular environment. Cytoplasm: The cytoplasm is the aqueous content of a cell inside the plasma membrane but outside the nucleus. Nucleus: The nucleus the is largest of the organelles (subcellular structures), it contains the DNA, or genetic material, of the cell and thus directs the cell’s activities. 39 40  The cell membrane The cell membrane is also called the plasma membrane or plasmalemma It envelops the cell and is a thin, pliable, semi permeable and elastic structure that is only 7.5 to 10 nm thick.  It is composed almost entirely of proteins and lipids. The approximate composition is:  Proteins 55% Lipids (phospholipids 25%, cholesterol 13% and other lipids 4%) Carbohydrates 3% 41  Structure of cell membrane Sandwich model: Also called pauci molecular model. It was proposed by Hugh Davson and James Danielli in 1935. The model describes a phospholipid bilayer that lies between two layers of globular proteins.  The model is a ‘lipo­protein sandwich’, as the lipid layer was sandwiched between two protein layers. 42 43 Fluid Mosaic Model It was proposed by G.L. Nicholson and S.L. Singer in 1972. According to this model, proteins are embedded partially or completely in the phospholipid bilayer. 44 Apart from lipids and proteins, there are carbohydrates molecules on the exterior surface of the cell membrane They are found bound to either to proteins, forming glycoproteins or to lipids, forming glycolipids The fluid mosaic model identifies the cell membrane as a mosaic of phospholipids, cholesterol, proteins, and carbohydrates 45 46 47  The lipids of the cell membrane Phospholipids: It consists of a phosphorylated glycerol backbone (“head”) and two fatty acid “tails” The glycerol backbone is hydrophilic (water soluble), and the fatty acid tails are hydrophobic (water insoluble). Thus, phospholipid molecules have both hydrophilic and hydrophobic properties and are called amphipathic At an oil­water interface molecules of phospholipids form a monolayer and orient themselves so that the head dissolves in the water phase and the tails dissolve in the oil phase. 48 In cell membranes, phospholipids orient so that the lipid­soluble fatty acid tails face each other and the water­soluble glycerol heads point away from each other. This orientation creates a lipid bilayer The fat­soluble substances like oxygen, carbon dioxide and alcohol can pass through this lipid layer. 49 50 Cholesterol: Are tucked between the phospholipid molecules, where they prevent the fatty acid chains from packing together and crystallizing. This maintain both fluidity and the stability of the cell membrane. Through their spatial relationship with phospholipid molecules, cholesterol molecules also help stabilize the phospholipids’ position. 51  Proteins of the cell membranes They may be either integral or peripheral, depending on whether they span the membrane or whether they are present on only one side. Integral (transmembrane) proteins : Are embedded in, and anchored to the cell membrane by hydrophobic interactions (Amphipathic). They span the lipid bilayer one or more times; thus, they are in contact with both ECF and ICF. 52 Examples of transmembrane integral proteins are:  Ligand­binding receptors, Transport proteins, Ion channels, Cell adhesion molecules GTP­binding proteins (G proteins) Surface antigens Enzymes Other integral proteins are embedded in the membrane but do not span it. 53 Peripheral membrane proteins: Are not embedded in the membrane and are not covalently bound to cell membrane components. They are loosely attached to either the intracellular or extracellular side of the cell membrane by electrostatic interactions (Not amphipathic). Example of peripheral membrane protein is ankyrin, which “anchors” the cytoskeleton of red blood cells to an integral membrane transport protein. 54 Carbohydrates of the cell membrane A small amount of membrane carbohydrate is located on the outer surface of cells, forming “sugar coat” known as glycocalyx. Short carbohydrate chains protrude like tiny antennas from the outer surface bound primarily to membrane proteins and to a lesser extent, to lipids Glycocalyx cushions the plasma membrane and protects it from physical and chemical injury It enables the immune system to recognize and selectively attack foreign organisms 55 Changes in the glycocalyx of cancerous cells enable the immune system to recognize and destroy them It forms the basis for compatibility of blood transfusions, tissue grafts, and organ transplants It binds cells together so tissues do not fall apart It enables sperm to recognize and bind to eggs It guides embryonic cells to their destinations in the body. 56 57  SHORT GUN  If viruses are considered living entities, which tenet of cell theory would not be acceptable? Amoeba, which is a unicellular organism, can be used to form a multicelluar organism T/F If the orientation of phospholipid bilayer is reversed, such that the head face the tail, can water soluble substances pass through T/F The self identity marker in a cell is ­­­­­­­­­­­­  Which of the following does not describe cell a. Honey comb b. Small blocks c. Bladders of air d. none of the options 58  Cytoplasm and its organelles The cytoplasm is that portion of the cell interior not occupied by the nucleus. It is filled with organelles (little organs) and cytoskeleton (Structursl proteins) The jelly­like fluid portion of the cytoplasm in which the particles are dispersed is called cytosol (cell liquid) It contains mainly dissolved proteins, electrolytes, and glucose. Cell organelles perform specific metabolic tasks, and those surrounded by one or two layers of unit membrane are referred to as membranous organelles. 59 Endoplasmic reticulum (ER): literally means “little network within the cytoplasm.” It is a system of interconnected channels (tubules) called cisternae enclosed by a unit membrane??? It connects cell membrane with nuclear membrane ER is divided into two distinct types: Rough or granular ER Smooth or agranular ER 60 The outer surface of the rough ER membrane is studded with small particles that give it a “rough” or granular appearance. These particles are ribosomes, which are rRNA–protein complexes that synthesize proteins under the direction of nuclear DNA The mRNA carries the genetic message from the nucleus to the ribosome where protein synthesis takes place.  Not all ribosomes in the cell are attached to the rough ER. Unattached or “free” ribosomes are dispersed throughout the cytosol 61 The rough ER, in association with its ribosomes, synthesizes and releases various new proteins into the ER lumen (ER matrix) These proteins serve one of two purposes:  Some proteins are destined for export to the cell’s exterior as secretory products such as protein hormones or enzymes. Other proteins are used in constructing new plasma membrane or other cell structures such as lysosomes.  In contrast to the rough ER ribosomes, free ribosomes synthesize proteins that are used within the cytosol 62 The agranular endoplasmic reticulum does not contain ribosomes, so it is “smooth’’; as such, it is not involved in protein synthesis. It is the site of steroid synthesis in steroid­secreting cells (ovary, adrenal cortex, testes) It is also the site of detoxification processes in other cells (kidney and liver). A modified endoplasmic reticulum, the sarcoplasmic reticulum stores calcium used for contraction in skeletal and cardiac muscle. 63 64 The Golgi (complex) apparatus , is closely related to the ER The Golgi apparatus is usually composed of four or more stacked layers of thin, flat, enclosed vesicles (cisterner) lying near one side of the nucleus. This apparatus is prominent in secretory cells, where it is located on the side of the cell from which the secretory substances are extruded. Small “transport vesicles” (also called endoplasmic reticulum vesicles, or) continually pinch off from the endoplasmic reticulum and shortly thereafter fuse with the Golgi apparatus. 65 Within the Golgi complex, the “raw” proteins from the ER are modified into their final form, for example, by having a carbohydrate attached. The Golgi complex is responsible for sorting and segregating products according to their function and destination into Golgi vesicles (post office of the cell). Some vesicles bud off to become lysosomes Some migrate to the plasma membrane and fuse with it, contributing fresh protein and phospholipid to the membrane Some become secretory vesicles that store a cell product like digestive enzymes, hormones etc 66 67 Lysosomes are vesicular organelles that form by breaking off from the Golgi apparatus. They provide an intracellular digestive system that allows the cell to digest:  Damaged cellular structures Food particles that have been ingested by the cell Unwanted matter such as bacteria A lysosome contains about 40 different powerful hydrolytic enzymes, which catalyze hydrolysis of organic molecules 68 Lysosomes also digest and dispose of surplus or non­vital organelles (garbage system) and other cell components in order to recycle their nutrients to more important cell needs; This process is called autophagy Lysosomes also aid in a process of “cell suicide.” Some cells are meant to do a certain function and then destroy themselves by programmed cell death 69 Peroxisomes are similar physically to lysosomes, but they are budding off from the smooth ER rather than from the Golgi apparatus. They contain oxidases rather than hydrolases. Several of the oxidases form hydrogen peroxide (oxidant). The oxidation of toxic molecules by peroxisomes in this way is an important function of liver and kidney cells. Catalase??? 70 Mitochondria are called the “powerhouses???” of the cell. They extract energy from oxidation of digested food and transform it into a usable form for cell activities. Mitochondria generate about 90% of the energy that cells and accordingly, the whole body need to survive and function. A single cell may contain as few as a hundred or as many as several thousand mitochondria, depending on the energy needs of each particular cell type 71 Each mitochondrion is enclosed by a double membrane.  A smooth outer membrane that surrounds the mitochondrion itself, and an inner membrane.  The inner membrane forms a series of infoldings or shelves called cristae, which project into an inner cavity known as the matrix. The cristae contain enzymes that cause oxidation of the nutrients, thereby forming carbon dioxide and water and at the same time releasing energy in form of ATP??? in a process called oxidative phosphorylation. 72 73 The cell cytoskeleton is a network of fibrillar proteins organized into microfilaments, intermediate filaments and microtubules. These originate as precursor protein molecules synthesized by ribosomes in the cytoplasm. This elaborate protein network gives the cell its shape, provides for its internal organization, and regulates its various movements.  in muscle cells, actin and myosin filaments are organized into a special contractile machine that is the basis for muscle contraction A special type of stiff filament composed of polymerized tubulin molecules is used in all cells to construct strong tubular structures, the microtubules 74 A centriole is a short cylindrical assembly of microtubules arranged in nine groups of three microtubules each. Two centrioles lie perpendicular to each other within a small clear area of cytoplasm called the centrosome. They are responsible for the movement of chromosomes during cell division 75 76 The nucleus is the largest organelle first discovered by Robert Brown in 1831. It contains the cell’s chromosomes and is therefore the genetic control centre of cellular activity. The nucleus can be distinguished by the two unit membranes surrounding it, which together form the nuclear envelope. The envelope is perforated with nuclear pores 77 The material in the nucleus is called nucleoplasm. This includes chromatin, fine threadlike matter composed of DNA, protein and one or more dark­staining masses called nucleoli where ribosomes are produced. The nucleus houses the cell’s genetic material, deoxyribonucleic acid (DNA), which has two important functions:  Directing protein synthesis and  Serving as a genetic blueprint during cell replication.  DNA provides codes, or instructions, for directing synthesis of specific structural and enzymatic proteins within the cell. By specifying the kinds and amounts of proteins that are produced, the nucleus indirectly governs most cell activities and serves as the cell’s control centre. 78 DNA consists of a chain of deoxyribose sugar linked to a phosphate groups through ester bond. Then attached by N­glycosidic linkage to an organic base, which may be adenine (A), guanine (G), thymine (T), or cytosine (C) (Neucleotide) In the cell, DNA forms a double helix of two strands oriented in opposite directions.  Each A on one strand pairing with a T on the complementary strand and each G pairing with a C 79 For the information encoded in the DNA to guide protein synthesis, a complementary strand of RNA must be synthesized to serve as the template The synthesis of RNA transfers encoded information from DNA to RNA and is therefore called transcription RNA sugar is ribose instead of deoxyribose, and it contains uracil (U) instead of thymine. The RNA transcript that emerges from the nucleus to direct synthesis of one or more proteins is called mRNA 80 81 82 The process of converting information carried by nucleic acids to proteins is called translation.  Each amino acid encoded in mRNA is specified by a codon of three adjacent nucleotides. Three types of ribonucleic acid (RNA) play roles in protein synthesis. First, DNA’s genetic code for a particular protein is transcribed into a messenger RNA (mRNA) molecule, which exits the nucleus through the nuclear pores 83 Within the cytoplasm, mRNA delivers the coded message to ribosomes, which “read” the code and translate it into the appropriate amino acid sequence for the designated protein being synthesized. Ribosomal RNA (rRNA) is an essential component of ribosomes.  Transfer RNA (tRNA) delivers the appropriate amino acids (anticodon???) within the cytoplasm to their designated site in the protein under construction. 84 85 Intercellular connections and communications  Cells can be connected to neighbouring cells or extracellular matrix by cell junctions. Intercellular junctions that form between the cells in tissues can be broadly split into two groups Junctions that fasten the cells to one another and to surrounding tissues Junctions that permit transfer of ions and other molecules from one cell to another 86 The types of junctions that tie cells together and endow tissues with strength and stability include: Tight junctions (zonula occludens) Desmosome Hemidesmosome Zonula adherens Focal adhesions 87 Tight Junction: Also called Zonula occludens Adjacent cells bind firmly with each other at points of direct contact (luminal or apical borders) to seal off the passageway between the two cells. It is impermeable and thus prevent materials from passing between the cells. There are three main families of transmembrane proteins that contribute to tight junctions: Occludin Junctional adhesion molecules (JAMs) Claudins; 88 Tight junctions permit the passage of some ions and solute in between adjacent cells (paracellular pathway) as “leakiness”. TJs surround the apical margins of the cells in epithelia such as the intestinal mucosa, the walls of the renal tubules and the choroid plexus. By holding the neighbouring cells of the tissues firmly, it provides strength and stability to the tissues.  They are also important to endothelial barrier function (BBB) 89 90 Desmosomes are adhering junctions. A desmosome consists of two components: A pair of dense, buttonlike cytoplasmic thickenings known as plaques located on the inner surface of each of the two adjacent cells; Strong filaments that contain a type of CAM, extend across the space between the two cells, and attach to the plaque on both sides. These intercellular filaments (Cadherins) bind adjacent plasma membranes together so that they resist being pulled apart. They are the strongest cell­to­cell connections and are most abundant in tissues that are subject to considerable stretching, such as those found in the skin, the heart, and the uterus. 91 92 Hemidesmosomes look like half­desmosomes that attach cells to the underlying basal lamina and are connected intracellularly to intermediate filaments. However, they contain integrins rather than cadherins. Zonula adherens connects the actin filaments of one cell to those of another cell. In adherens junction, the membranes of the adjacent cells are held together by some transmembrane proteins called cadherins. 93 They are also found in the intercalated disks Focal adhesions also attach cells to their basal laminas. They are labile structures associated with actin filaments inside the cell, and they play an important role in cell movement. 94  Communicating junctions The mechanisms via which cells communicate include: Direct communication between adjacent cells through gap junctions Autocrine and paracrine signaling, Release of neurotransmitters, hormones and neurohormones 95  Gap Junctions exists between adjacent cells, which are linked by small, connecting tunnels formed by connexons. A connexon is made up of six protein subunits called connexins arranged in a hollow tubelike structure that extends through the thickness of the plasma membrane. Two connexons, one from each of the plasma membranes of two adjacent cells, extend outward and join end to end to form a connecting tunnel between the two cells 96 97 98 99  Transport across cell membrane Whether or not a particle can permeate the plasma membrane depends on: The relative solubility of the particle in lipid bilayer  The size of the particle (Molecular weight) Temperature Surface area of the membrane Highly lipid­soluble particles can dissolve in the lipid bilayer and pass through the membrane Ions for which specific channels are available and open can permeate the membrane. Particles that have low lipid solubility and are too large for channels cannot permeate the membrane on their own 100 Substances may be transported down concentration or electrical (electrochemical???) gradient (downhill) or against an electrochemical gradient (uphill). Downhill transport (passive???) occurs by diffusion, either simple or facilitated and requires no input of metabolic energy. Uphill transport occurs by active transport, which may be primary or secondary. 101 Simple diffusion is the net movement of particles from a place of high concentration to a place of lower concentration as a result of their constant, spontaneous motion. Through lipid bilayer. The rate of diffusion of a substance through lipid bilayer of the membrane is directly proportional to its lipid solubility. Examples are oxygen, nitrogen, carbon dioxide, fatty acids, steroid hormones etc 102 Through protein channels: Water and ions are hydrophilic (lipophobic), and therefore highly insoluble in the membrane lipids. They readily diffuse through channels in protein molecules that penetrate all the way through the membrane (Integral membrane proteins). Water pass through channels in transmembrane proteins called aquaporins. 103  Ions like Na+, Ca2+, K+, Cl­ etc. pass through ion channels that are highly selective and specific. Some of the ion channels are gated (regulated) while others are non­gated (non­regulated). Gated ion channels Voltage­gated Ligand (chemical)­gated Mechanically­gated Non­gated ion channels (leak ion channels???). 104 Facilitated diffusion Like simple diffusion, facilitated diffusion occurs down an electrochemical potential gradient; thus, it requires no input of metabolic energy. Unlike simple diffusion however, facilitated diffusion uses a membrane carrier and exhibits all the characteristics of carrier­mediated transport. An example of facilitated diffusion is the transport of D­glucose into skeletal muscle and adipose cells by the GLUT4 transporter. 105 Glucose transport can proceed as long as the blood concentration of glucose is higher than the intracellular concentration of glucose and as long as the carriers are not saturated. All forms of carrier­mediated transport share the following three features: Saturation (Tm) Stereospecificity Competition 106 107  Active Transport In active transport, one or more solutes are moved against an electrochemical gradient (uphill). The solutes are moved from an area of low concentration (or low electrochemical) to an area of high concentration (or high electrochemical). Because movement of solute uphill is a work, metabolic energy in the form of ATP must be provided. 108  Primary active transport:  Energy is directly required to move a substance against its concentration gradient; the carrier splits ATP to power the transport process, Some substances that are transported by primary active transport include sodium, potassium, calcium, hydrogen, chloride etc. Examples of primary active transport: Na+/K+ ATPase (Na+­K+ pump) Ca2+ ATPase (Ca2+­pump) H+/K+ ATPase (H+­K+ pump) 109 The carrier acts as an enzyme that has ATPase activity The phosphate group then attaches to the carrier (phosphorylation), increasing the affinity of its binding site for the ion. As a result, the ion to be transported binds to the carrier on the low­concentration side.  In response to this binding, the carrier changes its conformation so that the ion is now exposed to the high­concentration side of the membrane.  The change in carrier shape reduces the affinity of the binding site for the passenger, so the ion is released on the high concentration side. Simultaneously, the change in shape is accompanied by dephosphorylation; that is, the phosphate group detaches from the carrier. 110 Na+/K+ ATPase (Na+-K+ pump) Na+/K+ ATPase is present in the membranes of all cells. It pumps Na+ from ICF to ECF and K+ from ECF to ICF. Each ion moves against its respective electrochemical gradient??? For every three Na+ ions pumped out of the cell, two K+ ions are pumped into the cell Thus, the process is termed electrogenic??? 111 112 The Na+­K+ ATPase is responsible for maintaining concentration gradients for both Na+ and K+ across cell membranes. By keeping the intracellular Na+ concentration low and the intracellular K+ concentration high??? Ca2+ ATPase (Ca2+ Pump):There are two types: Plasma­membrane Ca2+ ATPase (PMCA), whose function is to extrude Ca2+ from the cell against an electrochemical gradient; thereby maintaining the very low intracellular Ca2+ concentration. Sarcoplasmic reticulum Ca2+ ATPase (SERCA) is a variant of Ca2+ ATPase that pump two Ca2+ ions from intracellular fluid into the interior of the sarcoplasmic reticulum. 113 H+-K+ ATPase (H+-K+ Pump) H+­K+ ATPase is found in the parietal cells of the gastric mucosa and in the intercalated cells of the renal collecting duct. In the stomach, it pumps H+ from the ICF of the parietal cells into the lumen of the stomach. In the renal tubules, it is responsible for secretion of H+ from blood into the urine. 114  Secondary Active Transport. Secondary active transport processes are those in which the transport of two or more solutes is coupled. One of the solutes, usually Na+, moves down its electrochemical gradient (downhill), and the other solute moves against its electrochemical gradient (uphill). The downhill movement of Na+ provides energy for the uphill movement of the other solute. Thus, metabolic energy, as ATP, is not used directly, but it is supplied indirectly in the Na+ concentration gradient across the cell membrane maintained by Na­K ATPase. 115 There are two types of secondary active transport, distinguishable by the direction of movement of the uphill solute. If the uphill solute moves in the same direction as Na+, it is called cotransport or symport. If the uphill solute moves in the opposite direction of Na+, it is called countertransport, antiport, or exchange. 116 Examples of Na cotransports are Na­glucose transport (SGLT), Na­amino acid transport, Na­K­2Cl transports, Examples of Na antiports are Na­H exchanger and Na­Ca counter transport. Special categories of active transport:  Endocytosis  Exocytosis Transcytosis 117 118 119 Endocytosis is the specialized function of the cell membrane where very large particles enter the cell. It can be pinnocytosis (ingestion of minute particles in solution) or Phagocytosis (engulfing large particles i,e bacteria or dead tissue) Exocytosis is the export of materials out of the cell. It can be non­constitutive (regulated, processed) or constitutive (non­regulated) Transcytosis: a macromolecule enters through one side of a cell, migrates across cytoplasm of the cell and exits through the other side. 120 121  Establishment of Resting Membrane Potential Membrane potential refers to a separation of opposite charges across the membrane or to a difference in the relative number of cations and anions in the ICF and ECF. It is measured in millivolt (mV) which is usually negative. The negative sign means there are more negatively charged particles on the inside of the membrane than on the outside. 122  Resting Membrane Potential (Rmp)  It is also called Transmembrane potential  It is the potential difference that exists across the membrane of cells, when they are electrically at rest and not producing any electrical signals.  Cells have RMP because electrolytes (ions) are unequally distributed between the ECF on the outside of the plasma membrane and the ICF on the inside.  This creates a concentration (chemical) and electrical gradients across the plasma membrane.??? 123  RMP results from the combined effect of three factors:  The diffusion of ions down their concentration gradients through the membrane  Selective permeability of the membrane, allowing some ions to pass more easily than others  The electrical attraction of cations and anions to each other 124 There are more Na+ in ECF compared to ICF, while K+ is more in the ICF compared to the ECF. The outward K+ concentration gradient results in passive movement of K+ out of the cell when K+ leak channels are opened. Similarly, the inward Na+ concentration gradient results in passive movement of Na+ into the cell when Na+ leak channels are opened. 125 Factors that maintain RMP  Leak ion channels that allow intracellular movement of Na+ and Cl­, and extracellular movement of K+ along concentration gradients.  Anions in the cytoplasm that cannot escape from the cell because of their size or charge such as phosphates, sulfates, small organic acids, proteins, ATP, and RNA  The activity of sodium­potassium pump (Na+/K+ ATPase). It is an electrogenic pump that actively transports 3 sodium ions out of the cell, into the ECF, in exchange for 2 potassium ions into the ICF 126 127 128 129