FHS300 Cytology and Human Cell Pathology Lecture Notes PDF

FHS300 Cytology and Human Cell Pathology Dr. Rima Kamel School of Medicine and Medical Sciences © USEK 2024-2025 Course Outline Chapter 1: Introduction to Cytology Chapter 10: Cytopathology diagnostic...

FHS300 Cytology and Human Cell Pathology Dr. Rima Kamel School of Medicine and Medical Sciences © USEK 2024-2025 Course Outline Chapter 1: Introduction to Cytology Chapter 10: Cytopathology diagnostic techniques (the pap smear, exfoliative Chapter 2: Cell organelles (nucleus, cytology, body cavity fluids…) mitochondria, cytoskeleton…) Chapter 11: Cytopathology of body systems Chapter 3: Cell membrane and transport (respiratory, gastrointestinal, cardiovascular…) Chapter 4: Cell junctions and adhesion Chapter 12: Cerebrospinal Fluid and molecules Intraocular Cytopathology Chapter 5: Cell signaling Chapter 13: Cytopathology of glands (thyroid, salivary, adrenal) Chapter 6: Cell cycle and regulation Chapter 14: Cytopathology of soft tissue, bone Chapter 7: Oncogenes and tumor suppressors and skin genes p53 Chapter 15: Fine-needle aspiration of various Chapter 8: Apoptosis and Necrosis organs and body sites (Lymph nodes, lungs, liver, pancreas…) and Fine-Needle Aspiration Chapter 9: Methods and techniques in cell Cytology of Tumors of Unknown Origin biology Chapter 3 outline: Cell Membrane and Transport Functions of Membranes Biological membrane structure Lipids, the fluid part of the membrane: Phospholipids, glycolipids, sterols. Membrane asymmetry, lipid movement and membrane fluidity Proteins, the mosaic part of the membrane: Main classes of membrane proteins. Glycocalyx: Glycoproteins and glycolipids Transport across the membrane: simple diffusion, facilitated diffusion, active transport Movement of a solute and osmosis Transport proteins in facilitated diffusion Direct and indirect active transport The Functions of Membranes 1. Define boundaries of a cell and organelles and act as permeability barriers. They are effective permeability barriers because their interior is hydrophobic. 2. Serve as sites for biological functions, such as electron transport in the mitochondria or protein processing in the ER. 3. Possess transport proteins that regulate the movement of substances into and out of cells and organelles. 4. Contain protein molecules that act as receptors to detect external signals. 5. Provide mechanisms for cell-to-cell contact, adhesion, and communication. - Membranes are associated with specific functions because the molecules responsible for the functions are embedded in or localized on membranes. - The specific enzymes associated with particular membranes can be used to characterize a specific membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Functions of Membranes Figure 7.2 Functions of Membranes. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Biological Membrane Structure The fluid mosaic model is thought to be descriptive of all biological membranes. The model envisions a membrane as two fluid layers of lipids with proteins within and on the layers. It is fluid because lipids and proteins can easily move laterally in the membrane. It is mosaic because of the presence of proteins within the membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Protein, Lipid, and Carbohydrate Content of Biological Membranes Table 7.1 Protein and Lipid Content of Biological Membranes Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membrane Lipids: The “Fluid” Part of the Model Membrane lipids are important components of the “fluid” part of the fluid mosaic model. However, there is a great diversity and fluidity of lipids. The main classes of membrane lipids are phospholipids, glycolipids, and sterols. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Phospholipids (1 of 2) Phospholipids are the most abundant lipid in cell membranes. Phospholipid consists of a backbone with two fatty acids, a negatively charged phosphate group, and a charged head group attached to the phosphate. Amphipathic nature comes from the polar head and the two non-polar tails. This is critical for membrane structure. The backbone is either glycerol, a three-carbon alcohol, or sphingosine. Many types of phospholipids in membranes including the glycerol- based phosphoglycerolipids, phosphoglycerides, and the sphingosine-based phosphosphingolipids. Because phospholipids are amphipathic, other amphipathic molecules, like detergents, can disrupt membranes. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Phospholipids (2 of 2) Figure 7.6 The Three Major Classes of Membrane Lipids. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Glycolipids (1 of 2) Glycolipids are formed by the addition of carbohydrates to lipids. Some are glycerol based (the glycoglycerolipids), and some are sphingosine based (the glycosphingolipids). – The most common glycosphingolipids are cerebrosides and gangliosides. Cerebrosides are neutral glycolipids; each molecule has an uncharged sugar as its head group. A ganglioside has an oligosaccharide head group with one or more negatively charged sialic acid. Cerebrosides and gangliosides are especially prominent in brain and nerve cells. Gangliosides function as antigens on the plasma membrane surface. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Glycolipids (2 of 2) Figure 7.6 The Three Major Classes of Membrane Lipids. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Sterols The membranes of most eukaryotes contain significant amounts of sterols. The main sterol in animal cell membranes is cholesterol, which is needed to stabilize and maintain membranes. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Fatty Acids Are Essential to Membrane Structure and Function Fatty acids are components of all membrane lipids except the sterols. Their long hydrocarbon tails provide a barrier to diffusion of polar solutes. The sizes of membrane fatty acids range between 12 and 20 carbons long, which is optimal for bilayer formation and dictates the usual thickness of membranes (6–8 nm). Fatty acids vary considerably in the presence and number of double bonds. Palmitate (16 carbons) and stearate (18 carbons) are common saturated fatty acids. Oleate (one double bond) and linoleate (two double bonds) are both 18-carbon unsaturated fatty acids. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Polyunsaturated Fatty Acids Polyunsaturated fatty acids have more than one double bond. Polyunsaturated fatty acids found in membranes include linoleate, has 18 carbons and 3 double bonds (18:3) and arachidonate (20:4). Omega-3 fatty acids are polyunsaturated fatty acids with a double bond on the third carbon. They are essential for normal human development and may reduce the risk of heart disease. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membrane Asymmetry: Most Lipids Are Distributed Unequally Between the Two Monolayers Membrane asymmetry is the difference between the monolayers regarding the kind of lipids present and the degree of saturation of fatty acids in the phospholipids. Most of the glycolipids in the plasma membrane of animal cells are in the outer layer. Membrane asymmetry is established during the synthesis of the membrane. Once established, membrane asymmetry does not change much. The movement of lipids from one monolayer to another requires their hydrophilic heads to move all the way through the hydrophobic interior of the bilayer. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Lipids Move Freely Within Their Monolayer To maintain membrane asymmetry, lipids are mobile within their monolayer. – Rotation of phospholipids about their axes can occur. – Phospholipids can also move within the monolayer, via lateral diffusion. Both types of movement are rapid and random. – And, transverse diffusion (or “flip-flop”) which is relatively rare. Though rare, phospholipid flip-flop does occur in natural membranes. Some membranes, in particular the smooth ER membrane, have proteins that catalyze the flip-flop of membrane lipids. These proteins are called phospholipid translocators, or flippases. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Movements of Phospholipid Molecules Within Membranes Figure 7.10 Movements of Phospholipid Molecules Within Membranes. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membranes Function Properly Only in the Fluid State Membrane fluidity changes with temperature, decreasing as temperature falls and vice versa. Every lipid bilayer has a characteristic transition temperature Tm, the temperature at which it becomes fluid. This change of state is called a phase transition, in this case from solid to liquid. Below the Tm, any functions that rely on membrane fluidity will be disrupted. Fluidity of a membrane depends mainly on the fatty acids that it contains. The length of fatty acid chains and the degree of saturation both affect the fluidity of the membrane. Long-chain and saturated fatty acids have higher Tm values, whereas short-chain and unsaturated fatty acids have lower Tm values. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Fatty Acid Saturation and Membrane Fluidity Saturated fatty acids pack together well in the membrane. Fatty acids with one or more double bonds have bends in the chains that prevent them from packing together neatly. Thus, unsaturated fatty acids are more fluid than saturated fatty acids and have lower Tm values. Figure 7.12 Chain Length and Degree of Unsaturation Affect the Melting Point of Fatty Acids. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Effect of Unsaturated Fatty Acids on the Packing of Membrane Lipids Figure 7.13 The Effect of Unsaturated Fatty Acids on the Packing of Membrane Lipids. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Effects of Sterols on Membrane Fluidity and other effects Membrane fluidity is influenced by sterols (hydrogen bonds with phospholipids). The intercalation of rigid cholesterol molecules into a membrane decreases its fluidity and increases the Tm. However, cholesterol also prevents hydrocarbon chains of phospholipids from packing together tightly and so reduces the tendency of membranes to gel upon cooling. Therefore, cholesterol is a fluidity buffer. Sterols decrease the permeability of membranes to ions and small polar molecules. This is likely because they fill spaces between the hydrocarbon chains of phospholipids. This effectively blocks the routes that ions and small molecules would take through the membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membranes Contain Integral, Peripheral, and Lipid-Anchored Proteins The mosaic part of the fluid mosaic model includes lipid domains. However, membrane proteins are the main components. Membrane proteins have different hydrophobicities and so occupy different positions in or on membranes. This, in turn, determines how easily such proteins can be extracted from membranes. Membrane proteins fall into three categories: integral, peripheral, and lipid anchored. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Classes of Membrane Proteins 1. Integral membrane proteins are embedded in the lipid bilayer because of their hydrophobic regions. Some integral membrane proteins, called integral monotopic proteins, are embedded in just one side of the bilayer. However, most are transmembrane proteins that span the membrane and protrude on both sides. Transmembrane proteins cross either once (singlepass proteins) or several times (multipass proteins). 2. Peripheral proteins are hydrophilic and located on the surface of the bilayer. These peripheral membrane proteins are bound to membrane surfaces through weak electrostatic forces and hydrogen bonds. Some hydrophobic residues play a role in anchoring them to the membrane surface. 3. Lipid-anchored proteins are hydrophilic and attached to the bilayer by covalent attachments to lipid molecules (fatty acids: myristic acid or palmitic acid, isoprenyl groups or GPI: glycosylphosphatidylinositol) embedded in the bilayer. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Main Classes of Membrane Proteins Figure 7.17 The Main Classes of Membrane Proteins. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membrane Proteins Are Oriented Asymmetrically Across the Lipid Bilayer Membrane proteins exhibit asymmetric orientation with respect to the lipid bilayer. Once in place, in or on one of the monolayers, proteins cannot move across the membrane from one surface to the other. All the molecules of a particular protein are oriented the same way in the membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Many Membrane Proteins and Lipids Are Glycosylated Many membranes contain small amounts of carbohydrates. Glycoproteins are membrane proteins with carbohydrate chains covalently linked to amino acid side chains. The addition of a carbohydrate side chain to a protein is called glycosylation. Glycosylation occurs in the ER and Golgi compartments. Glycosylation involves linkage of the carbohydrate to either: – The nitrogen atom of an amino group (N-linked glycosylation) of an asparagine residue. – The oxygen atom of a hydroxl group (O-linked glycosylation) of a serine, threonine, or modified lysine or proline residue (hydroxylysine or hydroxyproline). Carbohydrate chains attached to peptides can be either straight or branched and range in length from 2 to about 60 sugar units. The most common sugars are galactose, mannose, N-acetylglucosamine, and sialic acid. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Roles of Glycoproteins and Glycolipids Glycoproteins: – Are most prominent in plasma membranes, where they play a role in cell-cell recognition. – The carbohydrate groups protrude on the outer surface of the cell membrane. Glycolipids: – Play a role in cell-cell recognition. – The ABO blood group system depends on genetically determined structural differences in the branched carbohydrate attached to a specific glycolipid in red blood cells. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Glycocalyx In animal cells, the carbohydrate groups of plasma membrane glycoproteins and glycolipids form a surface coat called a glycocalyx. Functions of the glycocalyx include cell-cell recognition and adhesion, protection of the cell surface, and the creation of permeability barriers. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Membrane Proteins Vary in Their Mobility Membrane proteins are more variable than lipids in their ability to move freely within the membrane and in their diffusion rates. Some proteins can move freely, whereas others are constrained because they are anchored to protein complexes or to structures to one side of the membrane or the other. For example, many proteins of the plasma membrane are anchored either to cytoskeleton or to extracellular structures. Membrane proteins aggregate within the membrane, forming large, slow-moving complexes. These structures can become barriers to diffusion, creating membrane domains. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Transport Across Membranes: Overcoming the Permeability Barrier Overcoming the permeability barrier of cell membranes is crucial to proper functioning of the cell. Specific molecules and ions need to be selectively moved into and out of the cell or organelle. Membranes are selectively permeable or semipermeable. Cells and cellular compartments accumulate a variety of substances in concentrations that are very different from those of the surroundings. This process is known as homeostasis. Most of the substances that move across membranes are dissolved gases, ions, and small organic molecules; these are solutes. A central aspect of cell function is selective transport, the movement of ions or organic molecules. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Transport Processes Within a Composite Eukaryotic Cell Figure 8.1 Transport Processes Within a Composite Eukaryotic Cell. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Solutes Cross Membranes by Simple Diffusion, Facilitated Diffusion, and Active Transport Three quite different mechanisms are involved in moving solutes across membranes. A few molecules cross membranes by simple diffusion, the direct unaided movement dictated by differences in concentration of the solute on the two sides of the membrane. However, most solutes cannot cross the membrane this way. Transport proteins assist most solutes across membranes. – These integral membrane proteins recognize with great specificity the substances to be transported. Some move solutes to regions of lower concentration; this facilitated diffusion (or passive transport) uses no energy. – In other cases, transport proteins move solutes against the concentration gradient; this is called active transport. Active transport requires energy such as that released by the hydrolysis of ATPor by the simultaneous transport of another solute down an energy gradient. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Comparison of Simple Diffusion, Facilitated Diffusion, and Active Transport Table 8.1 Comparison of Simple Diffusion, Facilitated Diffusion, and Active Transport Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Movement of a solute The Movement of a Solute Across a Membrane Is Determined by Its Concentration Gradient or Its Electrochemical Potential. –The movement of a molecule that has no net charge is determined by its concentration gradient. – The movement of an ion is determined by its electrochemical potential, the combined effect of its concentration gradient and the charge gradient across the membrane. The active transport of ions across a membrane creates a charge gradient, or membrane potential (Vm), across the membrane. Active Transport of Ions Most cells have an excess of negatively charged solutes inside the cell. This charge difference favors the inward movement of cations such as Na+ and outward movement of anions such as Cl–. In all organisms, active transport of ions across the plasma membrane results in asymmetric distribution of ions inside and outside the cell. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Erythrocyte Plasma Membrane Provides Examples of Transport Mechanisms The transport proteins of the erythrocyte plasma membrane are among the best understood of all such proteins. The membrane potential is maintained by active transport of potassium ions inward and sodium ions outward. Special pores, or channels, allow water and ions to enter or leave the cell rapidly as needed. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Important Transport Processes of the Erythrocyte Figure 8.2 Important Transport Processes of the Erythrocyte. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Simple diffusion: Oxygen and the Function of Erythrocytes Oxygen gas traverses the lipid bilayer readily by simple diffusion. Erythrocytes take up oxygen in the lungs, where oxygen concentration is high, and release it in the body tissues, where oxygen concentration is low. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Directions of Oxygen, Carbon Dioxide, and Bicarbonate Transport in Erythrocytes Figure 8.3 Directions of Oxygen, Carbon Dioxide, and Bicarbonate Transport in Erythrocytes. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Simple Diffusion Always Moves Solutes Toward Equilibrium Diffusion always tends to create a uniform solution in which the concentration is the same everywhere Solutes will move toward regions of lower concentration until the concentrations are equal Thus, diffusion is always movement toward equilibrium Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Osmosis Is the Diffusion of Water Across a Selectively Permeable Membrane Water molecules, being uncharged, are not affected by the membrane potential. Water concentration is not appreciably different on opposite sides of a membrane. Water will move across membranes in response to differences in solute concentration because the solutes themselves often do not readily cross the membranes. If two solutions are separated by a selectively permeable membrane, permeable to the water but not the solutes, the water will move toward the region of higher solute concentration. This movement is called osmosis. For most cells, water tends to move inward. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Comparison of Simple Diffusion and Osmosis Figure 8.4 Comparison of Simple Diffusion and Osmosis. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Osmolarity Osmotic movement into and out of a cell is related to the relative osmolarity, or total solute concentrations inside versus outside of the cell. If the solute concentration is higher outside the cell, the solution is called hypertonic. If the solute concentration is lower outside the cell, the solution is called hypotonic. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Cell Response to Osmolarity Cells tend to shrink or swell as the solute concentration of the extracellular medium changes. For example, an animal cell in an isotonic solution (same solute concentration inside and outside the cell) will shrink and shrivel if moved to a hypertonic solution. The same cell will swell and perhaps burst (or lyse) if placed in a very hypotonic solution. Cells solve the osmolarity problem by pumping out inorganic ions, reducing the intracellular osmolarity. This minimizes the intracellular osmolarity and the difference in solute concentration between the cell and the surroundings. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Transport Proteins in Facilitated Diffusion Most substances in the cell are too large or too polar to cross membranes by simple diffusion. These can move in and out of cells only with the assistance of transport proteins. No input of energy is needed in facilitated diffusion. The solute diffuses as dictated by its concentration gradient. The role of the transport proteins is just to provide a path through the lipid bilayer, allowing the “downhill” movement of a polar or charged solute. Facilitated diffusion can become saturated at high solute concentrations because there are a limited number of transport proteins. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Carrier Proteins and Channel Proteins Facilitate Diffusion by Different Mechanisms Transport proteins are large, integral membrane proteins with multiple transmembrane segments. Carrier proteins (transporters or permeases) bind solute molecules on one side of a membrane, undergo a conformation change, and release the solute on the other side of the membrane. Channel proteins form hydrophilic channels through the membrane to provide a passage route for solutes. – Some channels are large and nonspecific, such as the pores on the outer membranes of mitochondria. – Pores are formed by transmembrane proteins called porins that allow passage of solutes up to a certain molecular weight to pass (600). – Most channels are smaller and highly selective (most are ions channels, fast and does not require conformation changes). Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Carrier Proteins Alternate Between Two Conformational States The alternating conformation model states that a carrier protein is allosteric protein and alternates between two conformational states. In one state, the solute-binding site of the protein is accessible on one side of the membrane. The protein shifts to the alternate conformation, with the solute-binding site on the other side of the membrane, triggering solute release. Transport proteins are often highly specific for a single compound or a small group of closely related compounds. The carrier protein for glucose in erythrocytes is specific to a few monosaccharides and is stereospecific for only their D-isomers Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Competitive Inhibition of Carrier Proteins Competitive inhibition of carrier proteins can occur in the presence of molecules or ions that are structurally related to the correct substrate. For example, the transport of glucose by glucose carrier proteins can be inhibited by the other monosaccharides that the carrier accepts (such as mannose and galactose). Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Carrier Proteins Transport Either One or Two Solutes When a carrier protein transports a single solute across the membrane, the process is called uniport. A carrier protein that transports a single solute is called a uniporter. The glucose transporter is a uniport carrier for glucose. Copyright © 2022 Pearson Education Ltd. All Rights Reserved.  Coupled Transport When two solutes are transported simultaneously, and their transport is coupled, the process is called coupled transport. If the two solutes are moved across a membrane in the same direction, the process is referred to as symport (or cotransport). If the solutes are moved in opposite directions, the process is called antiport (or countertransport). Transporters that mediate these processes are symporters and antiporters. The anion exchange protein is an antiport anion carrier for Cl– and HCO3–. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Glucose Transporter: A Uniport Carrier The erythrocyte is capable of glucose uptake by facilitated diffusion because the level of blood glucose is much higher than that inside the cell. Glucose is transported inward by a glucose transporter (GLUT; GLUT1 in erythrocytes). GLUT1 is an integral membrane protein with 12 transmembrane segments, which form a cavity with hydrophilic side chains. GLUT1 is thought to transport glucose through the membrane by the alternating conformation mechanism. One conformational state, T1, has the binding site for glucose open on the outside of the cell. The other conformational state, T2, has the binding site open to the inside of the cell. A carrier protein can facilitate transport in either direction. The direction of transport is dictated by the relative solute concentrations outside and inside the cell. Glucose concentration is kept low inside most animal cells. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Alternating Conformation Model for Facilitated Diffusion of Glucose by the Glucose Transporter GLUT1 in the Erythrocyte Membrane Figure 8.8 The Alternating Conformation Model for Facilitated Diffusion of Glucose by the Glucose Transporter GLUT1 in the Erythrocyte Membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Phosphorylation of Glucose The immediate phosphorylation of glucose upon entry into the cell keeps the internal concentration of glucose low. Once phosphorylated, glucose cannot bind the carrier protein any longer and is effectively locked into the cell. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Erythrocyte Anion Exchange Protein: An Antiport Carrier The anion exchange protein (also called the chloride- bicarbonate exchanger) facilitates reciprocal exchange of Cl– and HCO3– ions only. Exchange will stop if either anion is absent. The ions are exchanged in a strict 1:1 ratio. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The “Ping-Pong” Mechanism The anion exchange protein is thought to alternate between two conformational states. In the first state, the protein binds a chloride ion on one side of the membrane, which causes a change to the second state. In the second state, the chloride is moved across the membrane and released. The release of chloride causes the protein to bind bicarbonate. The binding of bicarbonate causes a shift back to the first conformation. In this conformation, bicarbonate is moved out of the cell, allowing the carrier to bind chloride again. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Biological Relevance of Anion Exchange In tissues, waste CO2 diffuses into the erythrocytes, where it is converted to HCO3– by the enzyme carbonic anhydrase. As the concentration of bicarbonate rises, it moves out of the cell, coupled with uptake of Cl– to prevent a net charge imbalance. In the lungs, the entire process is reversed. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Channel Proteins Facilitate Diffusion by Forming Hydrophilic Transmembrane Channels Channel proteins form hydrophilic transmembrane channels that allow specific solutes to cross the membrane directly. There are three types of channels: ion channels, porins, and aquaporins. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Ion Channels: Transmembrane Proteins That Allow Rapid Passage of Specific Ions Ion channels, tiny pores lined with hydrophilic atoms, are remarkably selective. Because most allow passage of just one ion, separate proteins are needed to transport Na+, K+, Ca2+, and Cl–, etc. Selectivity is based both on binding sites involving amino acid side chains and on a size filter. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Gated Channels Most ion channels are gated, meaning that they open and close in response to some stimulus – Voltage-gated channels open and close in response to changes in membrane potential. – Ligand-gated channels are triggered by the binding of certain substances to the channel protein. – Mechanosensitive channels respond to mechanical forces acting on the membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Functions of Ion Channels Ion channels play roles in many types of cellular communication, such as muscle contraction and electrical signaling of nerve cells. Ion channels are also needed for maintaining salt balance in cells and airways linking the lungs. – A chloride ion channel, the cystic fibrosis transmembrane conductance regulator (CFTR), helps maintain the proper Cl– concentration in lungs; defects in the protein cause cystic fibrosis. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Porins: Transmembrane Proteins That Allow Rapid Passage of Various Solutes Pores on outer membranes mitochondria are larger and less specific than ion channels. The pores are formed by multipass transmembrane proteins called porins. The transmembrane segments of porins cross the membrane as β barrels. The β barrel has a water-filled pore at its center. Polar side chains line the inside of the pore, allowing passage of many hydrophilic solutes. The outside of the barrel contains many nonpolar side chains that interact with the hydrophobic interior of the membrane. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Aquaporins: Transmembrane Channels That Allow Rapid Passage of Water Movement of water across cell membranes in some tissues is faster than expected given the polarity of the water molecule. Aquaporin (AQP) was discovered only in 1992. Aquaporins allow rapid passage of water through membranes of erythrocytes and kidney cells in animal cells. The channels, lined with hydrophilic side chains, are just large enough for water molecules to pass through one at a time. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Active Transport: Protein-Mediated Movement up the Gradient Facilitated diffusion is important but accounts only for movement of molecules down a concentration gradient, toward equilibrium. Sometimes a substance must be transported against a concentration gradient. In this case, active transport is used to move solutes up a concentration gradient, away from equilibrium. Active transport allows the creation and maintenance of an internal cellular environment that differs greatly from the surrounding environment. Many membrane proteins involved in active transport are called pumps, because energy is required to move substances against their concentration gradients. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Functions of Active Transport Active transport couples endergonic transport to an exergonic process, usually ATP hydrolysis. Active transport performs three important cellular functions: – Uptake of essential nutrients – Removal of wastes – Maintenance of nonequilibrium concentrations of certain ions. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Active Transport Is Unidirectional Active transport differs from diffusion (both simple and facilitated) in the direction of transport. Diffusion is nondirectional with respect to the membrane and proceeds as directed by the concentrations of the transported substances. Active transport has an intrinsic directionality. Copyright © 2022 Pearson Education Ltd. All Rights Reserved.  The Coupling of Active Transport to an Energy Source May Be Direct or Indirect Active transport mechanisms can be divided based on the sources of energy and whether two solutes are transported at the same time. Active transport is categorized as direct or indirect. Direct active transport (primary active transport), the accumulation of solute molecules on one side of the membrane is coupled directly to an exergonic chemical reaction (reaction that releases free energy). – This is usually hydrolysis of ATP. – Transport proteins driven by ATPhydrolysis are called transport ATPases or ATPase pumps. Indirect active transport depends on the simultaneous transport of two solutes. – Favorable movement of one solute down its gradient drives the unfavorable movement of the other up its gradient. – This can be a symport or an antiport, depending on whether the two molecules are transported in the same or different directions. – Most cells continuously pump either sodium ions or protons out of the cell (for example, the Na+/K+ pump in animals). The resulting high extracellular concentration of Na+ is a driving force for the uptake of sugars and amino acids.This is indirectly related to A T P because the pump that maintains the sodium ion gradient is driven by A T P. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Comparison of Direct and Indirect Active Transport Figure 8.11 Comparison of Direct and Indirect Active Transport. Copyright © 2022 Pearson Education Ltd. All Rights Reserved.  Direct Active Transport Depends on Four Types of Transport ATPases Four types of transport ATPases have been identified that differ in structure, mechanism, location, and roles: – P-type (roles in muscle contraction and the acidification of gastric juices in the stomach) – V-type (pump protons into organelles such as vesicles, lysosomes, Golgi complex…) – F-type (found in mitochondria, In the reverse direction, the ATPases are more accurately called ATP synthases. Not only can ATP be used as an energy source to generate ion gradients, but such gradients can be used as an energy source to synthesize ATP). – ABC-type ((ATP binding cassette) transporters; are medically important because some of them pump antibiotics or drugs out of cells, rendering the cell resistant to the drug. Some human tumors are resistant to drugs that normally inhibit growth of tumors; the resistant cells have high concentrations of an ABC transporter called MDR (multidrug resistance) transport protein. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. MDR Transport Protein MDR transport protein pumps hydrophobic drugs out of cells, reducing the cytoplasmic concentration and hence their effectiveness. Unlike most ABC transporters, MDR protein transports a wide range of chemically dissimilar drugs. The MDR protein of some bacteria renders them resistant to antibiotics by a similar mechanism. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. The Cystic Fibrosis Transporter CFTR, the transporter responsible for cystic fibrosis (when defective), is similar in sequence and structure to the core domains of ABC transporters. However, CFTR is an ion channel and does not use ATP to drive transport. Instead, it uses ATP to open the channel. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Examples of Active Transport The Na+/K+ ATPase (or pump) in all animal cells is a well understood example of direct active transport by a P-type ATPase. The Na+/glucose symporter is an example of indirect active transport. Copyright © 2022 Pearson Education Ltd. All Rights Reserved. Direct Active Transport: The Na+/K+ Pump Maintains Electrochemical Ion Gradients In a mammalian neuron, [K+] inside>>>[K+] outside and [Na+] inside