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CHAPTER 4 Transport of Substances Through Cell Membranes Differences between the composition of intracellular and extracellular fluids are caused by transport mecha- nisms of cell membranes. Major differences in co...

CHAPTER 4 Transport of Substances Through Cell Membranes Differences between the composition of intracellular and extracellular fluids are caused by transport mecha- nisms of cell membranes. Major differences in composi- tion include the following: Extracellular fluid has higher concentrations of so- dium, calcium, bicarbonate, and chloride, compared with intracellular fluid. Intracellular fluid has higher concentrations of po- tassium, phosphates, magnesium, and proteins com- pared with extracellular fluid. The Cell Membrane Consists of a Lipid Bilayer Containing Many Different Protein Molecules. The lipid bilayer constitutes a barrier for movement of most water-soluble substances. However, smaller, lipid- soluble substances can pass directly through the lipid bilayer. Protein molecules in the lipid bilayer constitute an alternate transport pathway for water- soluble substances. Channel proteins provide a watery pathway for movement of (mainly) ions across the membrane. Carrier proteins bind I with specific molecules and then undergo conformational changes that move molecules across the membrane. Transport Through the Cell Membrane Occurs Via Diffusion or Active Transport. Diffusion means random movement of molecules ei- ther through intermolecular spaces in the cell mem- brane or in combination with a carrier protein. The energy that causes diffusion is the energy of the nor- mal kinetic motion of matter. Active transport means movement of substances across the membrane in combination with a carrier protein and also against an electrochemical gradient. This process requires a source of energy in addition to kinetic energy. DIFFUSION (p. 47) Diffusion Is the Continual Movement of Molecules in Liquids or Gases. Diffusion through the cell membrane can be divided into the following two subtypes: Simple diffusion means that molecules move through a membrane without binding to carrier proteins. Simple diffusion can occur by way of two pathways: 31 32 UNIT II Membrane Physiology, Nerve, and Muscle (1) through the interstices of the lipid bilayer, and (2) through water-filled protein channels that span the cell membrane. Facilitated diffusion requires a carrier protein. The carrier protein aids in passage of molecules through the membrane, probably by binding chemically with them and shuttling them through the membrane in this form. The Rate of Diffusion of a Substance Through the Cell Membrane Is Directly Proportional to Its Lipid Solubility. The lipid solubilities of oxygen, nitrogen, carbon dioxide, anesthetic gases, and most alcohols are so high that they can diffuse directly through the lipid bilayer of the cell membrane. Water and Other Lipid-Insoluble Molecules, Mainly Ions, Diffuse Through Protein Channels in the Cell Membrane. Water readily penetrates the cell membrane and can also pass through transmembrane protein channels. Other lipid-insoluble molecules (mainly ions) of a sufficiently small size can pass through the water-filled protein channels. Protein Channels Have Selective Permeability for Transport of One or More Specific Molecules. The selective permeability of protein channels results from the characteristics of the channel itself, such as its diameter, its shape, and the nature of the electrical charges along its inner surfaces. Gating of Protein Channels Provides a Means for Controlling Their Permeability. The gates are thought to be molecular extensions of the transport protein, which can close over the channel opening or be lifted from the opening by a conformational change in the protein molecule itself. The opening and closing of gates are controlled in two principal ways: Voltage gating. In this instance, the molecular con- formation of the gate is controlled by the electrical potential across the cell membrane. For example, the normal negative charge on the inside of the cell membrane causes sodium gates to remain tightly closed. When the inside of the membrane loses its negative charge (i.e., becomes less negative), these gates open, allowing sodium ions to pass inward through the sodium channels. The opening of sodi- um channel gates initiates action potentials in nerve fibers. Chemical gating. Some protein channel gates are opened by the binding of another molecule with the protein, which causes a conformational change in the membrane protein that opens or closes the  Transport of Substances Through Cell Membranes 33 gate. This process is called chemical (or ligand) gating. One of the most important instances of chemical gating is the effect of acetylcholine on the “acetylcholine cation channel” of the neuro- muscular junction. Facilitated Diffusion Is Also Called Carrier-Mediated Diffusion. Molecules transported by facilitated diffusion usually cannot pass through the cell membrane without the assistance of a specific carrier protein. Facilitated diffusion involves the following two steps: (1) the molecule to be transported enters a blind-ended channel and binds to a specific recep- tor, and (2) a conformational change occurs in the carrier protein, so the channel now opens to the opposite side of the membrane where the molecule is deposited. Facilitated diffusion differs from simple diffusion in the following important way. The rate of simple diffusion increases proportionately with the concen- tration of the diffusing substance. With facilitated diffusion, the rate of diffusion approaches a maxi- mum value as the concentration of the substance in- creases. This maximum rate is dictated by the rate at which the carrier protein molecule can undergo the conformational change. Among the most important substances that cross cell membranes by facilitated diffusion are glucose and most of the amino acids. Factors That Affect Net Rate of Diffusion (p. 52) Substances Can Diffuse in Both Directions Through the Cell Membrane. Therefore, what is usually important is the net rate of diffusion of a substance in one direction. This net rate is determined by the following factors: Permeability. The permeability of a membrane for a given substance is expressed as the net rate of diffu- sion of the substance through each unit area of the membrane for a unit concentration difference be- tween the two sides of the membrane (when there are no electrical or pressure differences). Concentration difference. The rate of net diffusion through a cell membrane is proportional to the dif- ference in concentration of the diffusing substance on the two sides of the membrane. Electrical potential. If an electrical potential is ap- plied across a membrane, the ions move through the membrane because of their electrical charges. When large amounts of ions have moved through the 34 UNIT II Membrane Physiology, Nerve, and Muscle membrane, a concentration difference of the same ions develops in the direction opposite to the elec- trical potential difference. When the concentration difference rises to a sufficiently high level, the two effects balance each other, creating a state of electro- chemical equilibrium. The electrical difference that balances a given concentration difference can be cal- culated using the Nernst equation. Osmosis Across Selectively Permeable Mem- branes—“Net Diffusion” of Water (p. 53) Osmosis Is the Process of Net Movement of Water Caused by a Concentration Difference of Water. Water is the most abundant substance to diffuse through the cell membrane. However, the amount that diffuses in each direction is so precisely balanced under normal conditions that not even the slightest net movement of water molecules occurs. Therefore, the volume of a cell remains constant. However, a concentration difference for water can develop across a cell membrane. When this happens, net movement of water occurs across the 2 cell membrane, causing the cell to either swell or shrink, depending on the direction of the net movement. The pressure difference required to stop osmosis is the osmotic pressure. The Osmotic Pressure Exerted by Particles in a Solution Is Determined by the Number of Particles per Unit Volume of Fluid and Not by the Mass of the Particles. On average, the kinetic energy of each molecule or ion that strikes a membrane is about the same regardless of its molecular size. Consequently, the factor that determines the osmotic pressure of a solution is the concentration of the solution in terms of number of particles per unit volume but not in terms of the mass of the solute. The Osmole Expresses Concentration in Terms of Number of Particles. One osmole is 1 gram molecular weight of undissociated solute. Thus, 180 grams of glucose, which is 1 gram molecular weight of glucose, is equal to 1 osmole of glucose because glucose does not dissociate. A solution that has 1 osmole of solute dissolved in each kilogram of water is said to have an osmolality of 1 osmole per kilogram, and a solution that has 1/1000 osmole dissolved per kilogram has an osmolality of 1 milliosmole per kilogram. The normal /fluids is osmolality of the extracellular and intracellular c about 300 milliosmoles per kilogram, and the osmotic pressure of these fluids is about 5500 mm Hg.  Transport of Substances Through Cell Membranes 35 “ACTIVE TRANSPORT” OF SUBSTANCES THROUGH MEMBRANES (p. 54) Active Transport Can Move a Substance Against an Electrochemical Gradient. An electrochemical gradient is the sum of all the diffusion forces acting at the membrane. These forces include the forces caused by a concentration difference, an electrical difference, and a pressure difference. When a cell membrane moves a substance uphill against an electrochemical gradient, the process is called active transport. Active Transport Is Divided Into Two Types According to the Source of the Energy Used to Effect the Transport. In both instances of active transport, transport depends on carrier proteins that span the cell membrane, which is also true for facilitated diffusion. Primary active transport. The energy is derived di- rectly from the breakdown of adenosine triphos- phate (ATP) or some other high-energy phosphate compound. Secondary active transport. The energy is derived sec- ondarily from energy that has been stored in the form of ionic concentration differences between the two sides of a membrane, originally created by primary active transport. The sodium electrochemical gradi- ent drives most secondary active transport processes. Primary Active Transport (p. 55) The Sodium-Potassium Pump Transports Sodium Ions out of Cells and Potassium Ions Into Cells. The sodium-potassium (Na+-K+) pump, which is present in all cells of the body, is responsible for maintaining the sodium and potassium concentration differences across the cell membrane, as well as for establishing a negative electrical potential inside the cells. The pump operates in the following manner.C Three sodium ions bind to a carrier protein on the inside of the cell, and S two potassium ions bind to - the carrier protein on the outside of the cell. The carrier protein has adenosine triphosphatase (ATPase) activity, and the simultaneous binding of sodium and potassium ions causes the ATPase function of the protein to become activated. The ATPase function then cleaves one molecule of ATP, splitting it to form one molecule of adenosine diphosphate and liberating a high-energy phosphate bond of energy. ↑ ↓ This energy is then believed to cause a conformational change in the protein carrier molecule, extruding the sodium ions to the outside and the potassium ions to the inside. 36 UNIT II Membrane Physiology, Nerve, and Muscle The Na+-K+ Pump Controls Cell Volume. The Na+-K+ pump transports three molecules of sodium to the outside of the cell for every two molecules of potassium pumped to the inside. This continual net loss of ions from the cell interior initiates an osmotic force to move water out of the cell. Furthermore, when the cell begins to swell, the Na+-K+ pump is automatically activated, moving to the exterior still more ions that are carrying water with them. Therefore, the Na+-K+ pump performs a continual surveillance role in maintaining normal cell volume. Active Transport Saturates in the Same Way That Facilitated Diffusion Saturates. When the difference in concentration of the substance to be transported is small, the rate of transport rises approximately in proportion to the increase in concentration. At high concentrations, the rate of transport is limited by the rates at which the chemical reactions of binding, release, and protein carrier conformational changes can occur. Co-Transport and Counter-Transport Are Two Forms of Secondary Active Transport. When sodium ions are transported out of cells by primary active transport, a large concentration gradient of sodium normally develops. This gradient represents a storehouse of energy because the excess sodium outside the cell membrane is always attempting to diffuse to the cell interior. Co-transport. The diffusion energy of sodium can pull other substances along with the sodium (in the same direction) through the cell membrane using a special carrier protein. Counter-transport. The sodium ion and substance to be counter-transported move to opposite sides of the membrane, with sodium always moving to the cell interior. Here again, a protein carrier is required. Glucose and Amino Acids Can Be Transported Into Most Cells by Sodium Co-Transport. Transport carrier proteins have two binding sites on their exterior side—one for sodium and one for glucose or amino acids. Again, the concentration of sodium ions is relatively high on the outside and relatively low on the inside, providing the energy for the transport. A special property of transport proteins is that the conformational change that allows sodium movement to the cell interior does not occur until a glucose or amino acid molecule also attaches to its specific protein carrier. Calcium and Hydrogen Ions Can Be Transported Out of Cells Through the Sodium Counter-Transport Mechanism. Calcium counter-transport occurs in most cell mem- branes, with sodium ions-> moving to the cell interior  Transport of Substances Through Cell Membranes 37 and calcium ions - moving > to the exterior; both are bound to the same transport protein in a counter- transport mode. Hydrogen counter-transport occurs especially in the proximal tubules of the kidneys, where sodium ions move from the lumen of the tubule to the interior of the tubular cells, and hydrogen ions are counter- transported into the lumen. CHAPTER 5 Membrane Potentials and Action Potentials Electrical potentials exist across the membranes of essentially all cells of the body. In addition, nerve and muscle cells are “excitable,” which means they are capable of self-generating electrical impulses at their membranes. The present discussion is concerned with membrane potentials that are generated both at rest and during action potentials by nerve and muscle cells. BASIC PHYSICS OF MEMBRANE POTENTIALS (p. 61) A Concentration Difference of Ions Across a Selectively Permeable Membrane Can Produce a Membrane Potential. Potassium diffusion potential. The neuronal cell membrane is highly permeable to potassium ions compared with most other ions. Potassium ions tend to diffuse outward because of their high concentration inside the cell. Because potassium ions are positively charged, the loss of potassium ions from the cell creates a negative potential in- side the cell. This negative membrane potential is sufficiently great to block further net diffusion of potassium despite the high potassium ion concen- tration gradient. In the normal large mammalian nerve fiber, the potential difference required to stop further net diffusion of potassium is about −94 millivolts. Sodium diffusion potential. Now let us imagine that a cell membrane is permeable to sodium ions but not to any other ions. Sodium ions would diffuse into the cell because of the high sodium concentration out- side the cell. The diffusion of sodium ions into the cell would create a positive potential inside the cell. Within milliseconds the membrane potential would rise to a sufficiently high level to block further net diffusion of sodium ions into the cell. This poten- tial is about +61 millivolts for the large mammalian nerve fiber. The Nernst Equation Describes the Relation of Diffusion Potential to Concentration Difference. The membrane potential that prevents net diffusion of an ion in either direction through the membrane is called the 38  Membrane Potentials and Action Potentials 39 Nernst potential for that ion. The Nernst equation is as follows: Concentration inside EMF millivolts 61 × log z Concentration outside where EMF is the electromotive force in millivolts and z is the electrical charge of the ion (e.g., +1 for K+). The sign of the potential is positive (+) if the ion under consideration is a negative ion and negative (−) if it is a positive ion. The Goldman Equation Is Used to Calculate the Diffusion Potential When the Membrane Is Permeable to Several Different Ions. When the membrane is permeable to several different ions, the diffusion potential that develops depends on three factors: (1) the polarity of the electrical charge of each ion, (2) the permeability of the membrane (P) to each ion, and (3) the concentrations (C) of the respective ions on the inside (i) and outside (o) of the membrane. The Goldman equation is as follows: CNai PNa C Ki P K C Cl o P Cl EMF millivolts 61 × log CNao PNa CK oPK C Cl i P Cl Note the following features and implications of the Goldman equation: Sodium, potassium, and chloride ions are most im- portantly involved in the development of membrane potentials in neurons and muscle fibers, as well as in the neuronal cells in the central nervous system. The degree of importance of each ion in determining the voltage is proportional to the membrane perme- ability for that particular ion. A positive ion concentration gradient from inside the membrane to the outside causes electronegativ- ity inside the membrane. RESTING MEMBRANE POTENTIAL OF NEURONS (p. 63) The Resting Membrane Potential Is Established by the Diffusion Potentials, Membrane Permeability, and Electrogenic Nature of the Sodium-Potassium Pump. Potassium diffusion potential. A high ratio of potas- sium ions from inside to outside the cell, 35:1, pro- duces a Nernst potential of −94 millivolts according to the Nernst equation. Sodium diffusion potential. The ratio of sodium ions from inside to outside the membrane is 0.1, which yields a calculated Nernst potential of +61 millivolts. Membrane permeability. The permeability of the nerve fiber membrane to potassium is about 100 times 40 UNIT II Membrane Physiology, Nerve, and Muscle greater compared with sodium, so the diffusion of potassium contributes far more to the membrane potential. This high value of potassium permeability in the Goldman equation yields an internal mem- brane potential of −86 millivolts, which is close to the potassium diffusion potential of −94 millivolts. Electrogenic nature of the sodium-potassium (Na+- K+) pump. The Na+-K+ pump transports three so- dium ions to the outside of the cell for each two potassium ions pumped to the inside, which causes a continual loss of positive charges from inside the membrane. Therefore, the Na+-K+ pump is electro- genic because it produces a net deficit of positive ions inside the cell, which causes a negative charge of about −4 millivolts inside the cell membrane. NEURON ACTION POTENTIAL (p. 65) Neuronal signals are transmitted by action potentials, which are rapid changes in membrane potential. Each action potential begins with a sudden change from the normal resting negative potential to a positive mem- brane potential and then ends with an almost equally rapid change back to the resting negative potential. The successive stages of the action potential are as follows: Resting stage. This is the resting membrane potential before the action potential occurs. Depolarization stage. At this time, the membrane suddenly becomes permeable to sodium ions, allow- ing tremendous numbers of positively charged so- dium ions to move to the interior of the axon. This movement of sodium ions causes the membrane potential to rise rapidly in the positive direction. Repolarization stage. Within a few ten-thousandths of a second after the membrane becomes highly per- meable to sodium ions, the voltage-gated sodium channels begin to close and the voltage-gated potas- sium channels begin to open. Then rapid diffusion of potassium ions to the exterior re-establishes the normal negative resting membrane potential. Voltage-Gated Sodium and Potassium Channels Are Activated and Inactivated During the Course of an Action Potential. The voltage-gated sodium channel is necessary for both depolarization and repolarization of the neuronal membrane during an action potential. The voltage-gated potassium channel also plays an important role in increasing the rapidity of repolarization of the membrane. These two voltage-gated channels are present  Membrane Potentials and Action Potentials 41 in addition to the Na+-K+ pump and the Na+-K+ leak channels that establish the resting permeability of the membrane. Summary of the Events That Cause the Action Potential. During the resting state, before the action poten- tial begins, the conductance for potassium ions is about 100 times as great as the conductance for so- dium ions. This is caused by much greater leakage of potassium ions than sodium ions through the leak channels. At the onset of the action potential, the voltage-gated sodium channels instantaneously become activated and allow up to a 5000-fold increase in sodium per- meability (also called sodium conductance). The in- activation process then closes the sodium channels within a few fractions of a millisecond. The onset of the action potential also causes voltage gating of the potassium channels, causing them to begin opening more slowly. At the end of the action potential, the return of the membrane potential to the negative state causes the potassium channels to close back to their original status but, again, only after a delay. A Positive-Feedback, Vicious Cycle Opens the Sodium Channels. If any event causes the membrane potential to rise from −90 millivolts toward the zero level, the rising voltage itself causes many voltage-gated sodium channels to begin opening. This action allows rapid inflow of sodium ions, which causes still further rise of the membrane potential, thus opening still more voltage-gated sodium channels. This process is a positive-feedback vicious cycle that continues until all of the voltage-gated sodium channels have become activated (opened). An Action Potential Does Not Occur Until the Threshold Potential Has Been Reached. The threshold potential has been reached when the number of sodium ions entering the nerve fiber becomes greater than the number of potassium ions leaving the fiber. A sudden increase in the membrane potential in a large nerve fiber from −90 millivolts to about −65 millivolts usually causes explosive development of the action potential. This level of −65 millivolts is said to be the threshold of the membrane for stimulation. A New Action Potential Cannot Occur When the Membrane Is Still Depolarized From the Preceding Action Potential. Shortly after the action potential is initiated, the sodium channels become inactivated, and any amount of excitatory signal applied to these channels 42 UNIT II Membrane Physiology, Nerve, and Muscle at this point does not open the inactivation gates. The only condition that can reopen them is when the membrane potential returns either to or almost to the original resting membrane potential. Then, within another small fraction of a second, the inactivation gates of the channels open, and a new action potential can be initiated. Absolute refractory period. An action potential can- not be elicited during the absolute refractory period, even with a strong stimulus. This period for large myelinated nerve fibers is about 1/2500 second, which means that a maximum of about 2500 impuls- es can be transmitted per second. Relative refractory period. This period follows the absolute refractory period. During this time, stron- ger than normal stimuli are required to excite the nerve fiber and for an action potential to be initiated. PROPAGATION OF THE ACTION POTENTIAL (p. 69) An action potential elicited at any one point on a membrane usually excites adjacent portions of the membrane, resulting in propagation of the action potential. Thus, the depolarization process travels along the entire extent of the nerve fiber. Transmission of the depolarization process along a neuron or muscle fiber is called a neuronal or muscle impulse. Direction of propagation. An excitable membrane has no single direction of propagation; instead, the action potential travels in both directions away from the stimulus. Chemical synapses dictate directional- ity of action potentials. All-or-nothing principle. Once an action potential has been elicited at any point on the membrane of a normal fiber, the depolarization process travels over the entire membrane under normal conditions, or it might not travel at all if conditions are not normal. RE-ESTABLISHING SODIUM AND POTASSIUM IONIC GRADIENTS AFTER ACTION POTENTIALS ARE COMPLETED—IMPORTANCE OF ENERGY METABOLISM (p. 69) Transmission of each impulse along the nerve fiber reduces infinitesimally the concentration differences of sodium and potassium between the inside and outside of the membrane. From 100,000 to 50 million impulses can be transmitted by nerve fibers before the ion con- centration differences have decreased to the point that  Membrane Potentials and Action Potentials 43 action potentials cannot occur. Even so, with time it becomes necessary to re-establish the sodium and potassium concentration differences across the mem- brane, which is achieved by the Na+-K+ pump. SPECIAL CHARACTERISTICS OF SIGNAL TRANSMISSION IN NERVE TRUNKS (p. 71) Large Nerve Fibers Are Myelinated and Small Ones Are Unmyelinated. The central core of the fiber is the axon, 2 and the membrane of the axon is used for conducting the action potential. Surrounding the larger axons is a thick myelin sheath deposited by Schwann cells. The sheath consists of multiple layers of cellular membrane containing the lipid substance sphingomyelin, which < is an excellent insulator. At the juncture between two successive Schwann cells, a small noninsulated area only 2 to 3 micrometers in length remains where ions can still flow with ease between the extracellular fluid and the axon interior. This area is the node of Ranvier. “Saltatory” Conduction Occurs in Myelinated Fibers. Even though ions cannot flow significantly through the thick sheaths of myelinated neurons, they can flow with considerable ease through the nodes of Ranvier. Thus, the neuronal impulse jumps from node to node along the fiber, which is the origin of the term “saltatory.” Saltatory conduction is of value for two reasons: Increased velocity. By causing the depolarization process to jump long intervals (up to about 1.5 milli- meters) along the axis of the nerve fiber, this mecha- nism increases the velocity of neuronal transmission in myelinated fibers as much as 5- to 50-fold. Energy conservation. Saltatory conduction conserves energy for the axon because only the nodes depolarize, allowing perhaps a hundred times smaller movement of ions than would otherwise be necessary and there- fore requiring little energy for re-establishing the so- dium and potassium concentration differences across the membrane after a series of neuronal impulses. Conduction Velocity Is Greatest in Large, Myelinated Nerve Fibers. The velocity of action potential conduction in nerve fibers varies from as low as 0.25 m/sec in very small unmyelinated fibers to as high as 100 m/sec in very large myelinated fibers. The velocity increases approximately with the fiber diameter in myelinated nerve fibers and approximately with the square root of the fiber diameter in unmyelinated fibers.