Membrane Transport, Nerve, and Muscle (PDF)

Membrane Physiology Dr. Hiwa Shafiq Namiq MSc, PhD, Clinical Neurophysiologist Lecturer/Physiology 4-11-2024 Chemical compositions of extracellular and intracellular fluids. Diffusion of a molecule in a solution: All molecules and ions in the body fluids, inclu...

Membrane Physiology Dr. Hiwa Shafiq Namiq MSc, PhD, Clinical Neurophysiologist Lecturer/Physiology 4-11-2024 Chemical compositions of extracellular and intracellular fluids. Diffusion of a molecule in a solution: All molecules and ions in the body fluids, including water molecules and dissolved substances, are in constant motion, with each particle moving its separate way. The motion of these particles is what physicists call “heat”— the greater the motion, the higher the temperature—and the motion never ceases except at absolute zero temperature. Diffusion of a fluid molecule during a thousandth of a second. Transport through the cell membrane occurs by one of two basic processes: Diffusion and Active transport Diffusion through cell membrane Random molecular movement of substances either through intermolecular spaces in the membrane or in combination with a carrier protein. The energy that causes diffusion is the energy of the normal kinetic motion of the substance. A. Simple diffusion: Molecules or ions move either through a membrane opening (water and water-soluble molecules as ions, glucose, urea) or through intermolecular spaces (lipid soluble molecules as O2, CO2, alcohol) without any interaction with carrier proteins in the membrane. The rate of diffusion is determined by: 1.Amount of substance available 2.Velocity of kinetic motion 3.Number and sizes of openings in the membrane. B. Facilitated diffusion (carrier-mediated diffusion): ▪ A carrier protein aids passage of the molecules or ions through the membrane by binding chemically with them. ▪ Rate of diffusion approaches maximum as the concentration of the diffusing substance increases (Vmax). ▪ Glucose and most of the amino acids are transported by facilitated diffusion The postulated mechanism for facilitated diffusion Simple and facilitated diffusion.  DIFFUSION THROUGH PROTEIN PORES AND CHANNELS—SELECTIVE PERMEABILITY AND “GATING” OF CHANNELS The protein channels of cell membrane are distinguished by two important characteristics: (1) Selective permeable to certain substances (like sodium and potassium channels). (2) Open or close by gates. The opening and closing of gates are controlled in two principal ways: A. Voltage gating The channel opens in response to electrical potential change across the cell membrane. E.g. (Na channel opens when the inside of the membrane loses its negativity allowing tremendous quantities of sodium to pass inward. This is the basic mechanism for eliciting action potentials in nerves that are responsible for nerve signals) B. Chemical (ligand) gating In this case the channel is opened by the binding of a chemical substance (a ligand) with the protein E.g. Effect of acetylcholine on acetylcholine-gated sodium channels allowing passage of positive ions. This gate is exceedingly important for the transmission of nerve signals from one nerve cell to another and from nerve cells to muscle cells to cause muscle contraction. Transport of sodium and potassium ions through protein channels.  Active transport It means movement of ions or other substances across the membrane in combination with a carrier protein in such a way that the carrier protein causes the substance to move against an energy gradient (or “uphill” against an electrical or pressure gradient), such as from a low- concentration state to a high- concentration state. This movement requires a source of energy besides kinetic energy.  Different substances that are actively transported through some cell membranes include: sodium ions, potassium ions, calcium ions, iron, hydrogen ions, chloride ions, iodide ions, urate ions, several different sugars, and most of the amino acids.  Active transport is divided into: A. Primary active transport B. Secondary active transport In primary active transport, the energy is derived directly from breakdown of adenosine triphosphate (ATP). In secondary active transport, the energy is derived secondarily from energy that has been stored in the form of ionic concentration differences of substances between the two sides of a cell membrane, created originally by primary active transport. In both instances, transport depends on carrier proteins that penetrate through the cell membrane. The carrier protein is capable of imparting energy to the transported substance to move it against the electrochemical gradient.  Primary active transport: 1. Sodium-Potassium Pump It is a transport process that pumps 3 sodium ions outward through the cell membrane of all cells and at the same time pumps 2 potassium ions from the outside to the inside. The energy is derived from ATPase activity of the pump that cleaves one molecule of ATP, splitting it to adenosine diphosphate (ADP) and liberating a high-energy from phosphate bond.  This pump is responsible for maintaining the sodium and potassium concentration differences across the cell membrane, as well as for establishing a negative electrical voltage inside the cells. This pump is also the basis of nerve function, transmitting nerve signals throughout the nervous system. Finally this pump is also responsible for controlling cell volume The postulated mechanism of the sodium-potassium pump. ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi, phosphate ion 2. Ca pumps: Two Ca pumps are present: One is in the cell membrane and pumps calcium to the outside of the cell. The other pumps calcium ions into one or more of the intracellular vesicular organelles of the cell, such as the sarcoplasmic reticulum of muscle cells and the mitochondria in all cells. Both of the pumps function to maintain Ca ion concentration extremely low in the intracellular cytosol. 3. Hydrogen pump: Primary active transport of hydrogen ions is very important in two places: (1) Gastric glands of the stomach. (2) Distal tubules and cortical collecting ducts of the kidneys.  Secondary active transport Co-Transport and Counter-Transport A. Co-Transport Example: co-transport of glucose with sodium ion or amino acids with sodium ions. The postulated mechanism for sodium co-transport of glucose. B. Counter-transport Example: sodium counter-transport of calcium (all cells) and hydrogen ions(proximal tubules of kidney). Sodium counter-transport of calcium and hydrogen ions. Membrane potentials and Action potentials  RESTING MEMBRANE POTENTIAL OF NEURONS The resting membrane potential of large nerve fibers when they are not transmitting nerve signals is about−70 millivolts. That is, the potential inside the fiber is 70 millivolts more negative than the potential in the extracellular fluid on the outside of the fiber.  Nerve action potential Distribution of positively and negatively charged ions in the extracellular fluid surrounding a nerve fiber and in the fluid inside the fiber at rest. The lower panel displays the abrupt changes in membrane potential that occur at the membranes on the two sides of the fiber. The resting membrane potentials in neurons is typically between -50 to -75 mV Action potentials are rapid changes in the membrane potential that spread rapidly along the nerve fiber membrane (nerve impulse). Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and then ends with an almost equally rapid change back to the negative potential.  Stages of action potential in nerves Resting Stage (polarization stage): The resting stage is the resting membrane potential before the action potential begins. The membrane is said to be “polarized” during this stage because of the −70 millivolts negative membrane potential that is present. Depolarization Stage. The membrane suddenly becomes permeable to sodium ions, allowing rapid diffusion of positively charged sodium ions to the interior of the axon. The normal polarized state of −70 millivolts is immediately neutralized by the inflowing, positively charged sodium ions, with the potential rising rapidly in the positive direction—a process called depolarization. In large nerve fibers, the great excess of positive sodium ions moving to the inside causes the membrane potential to actually overshoot beyond the zero level and to become somewhat positive. In some smaller fibers, as well as in many central nervous system neurons, the potential merely approaches the zero level and does not overshoot to the positive state. Repolarization Stage. After the membrane becomes highly permeable to sodium ions, the sodium channels begin to close and the potassium channels open more than normal. Then, rapid diffusion of potassium ions to the exterior re- establishes the normal negative resting membrane potential. This is called repolarization of the membrane. Typical action potential  Initiation of the action potential If any event (mechanical disturbance of the membrane, chemical effects on the membrane, or passage of electricity through the membrane) causes enough initial rise in the membrane potential from –70 millivolts toward the zero level, many voltage- gated sodium channels start to open. This allows rapid inflow of sodium ions, which causes a further rise in the membrane potential, thus a vicious cycle occurs that continues until all the voltage-gated sodium channels have become activated (opened) (What kind of feedback mechanism?  Threshold for initiation of the action potential An action potential will not occur until the initial rise in membrane potential is great enough to create the positive feedback described for opening of sodium channels. This occurs when the number of sodium ions entering the fiber is greater than the number of potassium ions leaving the fiber. A sudden rise in membrane potential of 15 to 30 millivolts is usually required. Therefore, a sudden increase in the membrane potential in a large nerve fiber, from −70 millivolts up to about −55 millivolts, usually causes the explosive development of an action potential. This level of −55 millivolts is said to be the threshold for stimulation.  Propagation of the AP An action potential elicited at any point on an excitable membrane usually excites adjacent portions of the membrane, resulting in propagation of the action potential along the membrane. The depolarization process then travels along the entire length of the fiber in both directions. This transmission along a nerve or muscle fiber is called a nerve or muscle impulse.  Re-establishing sodium and potassium ionic gradients When the AP has completed, it becomes necessary to re-establish the sodium and potassium membrane concentration differences. That is, sodium ions that have diffused to the interior of the cell during the action potentials (depolarization stage) and potassium ions that have diffused to the exterior (repolarization stage) must be returned to their original state. This is achieved by action of the Na+-K+ pump.  Plateau in some action potentials In some instances, the excited membrane does not repolarize immediately after depolarization; instead, the potential remains on a plateau near the peak of the spike potential for many milliseconds, and only then does repolarization begin. This greatly prolongs the period of depolarization. This type of action potential occurs in heart muscle fibers, where the plateau lasts for as long as 0.2 to 0.3 second and causes contraction of heart muscle to last for this same long period.  Factors casing AP plateau 1. In heart muscle, two types of channels enter into the depolarization process: (1) the usual voltage-activated sodium channels, called fast channels, and (2) voltage- activated calcium-sodium channels, which are slow to open and therefore are called slow channels. 2. A second factor that may be partly responsible for the plateau is that the voltage-gated potassium channels are slower than usual to open, often not opening very much until the end of the plateau. Skeletal and Smooth Muscle Contraction  Skeletal Muscle Fiber About 40 per cent of the body is skeletal muscle, and 10 per cent is smooth and cardiac muscle. Skeletal muscles are composed of numerous fibers and each fiber is made up of successively smaller subunits. In most skeletal muscles, each fiber extends the entire length of the muscle. Except for about 2 per cent of the fibers, each fiber is usually innervated by only one nerve ending, located near the middle of the fiber. The cell membrane of the muscle fiber is called sarcolemma and the cytoplasm is called sarcoplasm. The sarcoplasmic reticulum is the endoplasmic reticulum of muscle fiber extremely important in muscle contraction.  Each muscle fiber consists of myofibrils (1500 myosin filaments and 3000 actin filaments) responsible for the actual muscle contraction. Myosin and actin filaments partially interdigitate causing myofibrils to have alternate light and dark bands (I bands and A bands) (striated appearance). The small projections from the sides of the myosin are called cross- bridges. It is the interaction between these cross-bridges and the actin filaments that causes contraction From the Z discs, actin filaments extend in both direction to interdigitate with the myosin. The portion of the myofibril that lies between two successive Z discs is called a sarcomere. The sarcomere shortens during muscle contraction to a degree that the actin filaments completely overlap the myosin filaments.  An action potential travels along a motor nerve to its endings on muscle fibers causing secretion of a small amount of acetylcholine After a fraction of a second, the calcium ions are pumped back The acetylcholine opens into the sarcoplasmic reticulum acetylcholine-gated Na by a Ca++ membrane pump channels causing muscle contraction to cease. Steps of skeletal Large quantities of sodium ions diffuse muscle contraction to the interior reducing the negative The calcium ions initiate potential inside muscle membrane attractive forces between the and initiating an AP actin and myosin filaments, causing them to slide alongside each other The AP causes the sarcoplasmic reticulum to The action potential release large quantities of travels along the calcium ions muscle fiber  Sliding filament mechanism of muscle contraction In the relaxed state, the ends of the actin filaments extending from two successive Z discs barely begin to overlap one another. Conversely, in the contracted state, these actin filaments have been pulled inward among the myosin filaments, so that their ends overlap one another to their maximum extent. Also, the Z discs have been pulled by the actin filaments up to the ends of the myosin filaments.  Sources of energy for muscle contraction Most of energy during muscle contraction is required to provide walk- along mechanism by which the cross-bridges pull the actin filaments. Some energy is also required for: 1- Pumping calcium ions from the sarcoplasm into the sarcoplasmic reticulum after the contraction is over. 2- Pumping sodium and potassium ions through the muscle fiber membrane to maintain appropriate ionic environment. The concentration of ATP in the muscle fiber is sufficient to maintain full contraction for only 1 to 2 seconds..  1. Glycolysis of glycogen This can occur in the absence of oxygen and is about 2.5 times as rapid as ATP formation than oxidative source, but it can only sustain 3. Oxidative metabolism. 2. Phosphocreatine source maximum muscle Is combining oxygen with the contraction for about 1 end products of glycolysis and The combined energy of minute. with carbohydrates, fats, and both the stored ATP and the protein to liberate ATP. phosphocreatine in the muscle is capable of causing More than 95 per cent of all energy used by the muscles for maximal muscle contraction sustained, long-term (many for only 5 to 8 seconds. hours) contraction is derived from this source. Sources of rephosphorylation Excitation of skeletal muscle The Neuromuscular junction  The skeletal muscle fibers are innervated by large, myelinated nerve fibers and each nerve ending makes a junction, called the neuromuscular junction, with the muscle fiber near its midpoint. Both the nerve terminals with muscle fiber plasma membrane together are called the motor end plate. When a nerve impulse reaches the neuromuscular junction, about 125 vesicles of acetylcholine are released from the terminals into the synaptic space (synaptic cleft). The acetylcholine in turn excites the muscle fiber membrane. When an action potential spreads over the terminal, calcium channels open and allow calcium ions to diffuse from the synaptic space to the interior of the nerve terminal causing fusion of Ach vesicles and Ach release by exocytosis.  When acetylcholine is emptied into the synaptic space, they bind to their receptor on the Ach-gated channels and thus opening the channel. After remaining for a few milliseconds in the synaptic space, the Ach is rapidly destroyed by the enzyme acetylcholinesterase to prevent continued muscle re-excitation.  Excitation-Contraction Coupling Transmission of action potential to the deeper region of the muscle fiber occurs along transverse tubules (T tubules) that penetrate all the way through the muscle fiber from one side of the fiber to the other. The T-tubules communicate with the extracellular fluid surrounding the muscle fiber, and they contain extracellular fluid in their lumens. When an action potential spreads over a muscle fiber membrane, a potential change also spreads along the T tubules to the deep interior of the muscle fiber. The T tubule action potentials cause release of calcium ions inside the muscle fiber and these calcium ions then cause contraction. This overall process is called excitation- contraction coupling. Then the Ca ions are pumped back into the sarcoplasmic reticulum. Smooth muscle  Smooth muscle composed of fibers that are both shorter and smaller than that of skeletal muscle. There are two major types of smooth muscles: 1. Multi-unit smooth muscle. 2. Single-unit (unitary) smooth muscle. Multi-unit smooth muscle Composed of discrete, separate smooth muscle fibers that operate independently of the other fibers. Often innervated by a single nerve ending. Controlled by nervous signal. Examples: Ciliary and iris muscles of the eye and piloerector muscle of the hair.  Single unit smooth muscle Arranged in a mass of hundreds to thousands of smooth muscle fibers that contract together as a single unit. The muscle cell membranes are adherent to one another so that force generated in one muscle fiber can be transmitted to the next. The cell membranes are joined by many gap junctions through which ions can flow freely from one muscle cell to the next so that action potentials can travel from one fiber to the next and cause the muscle fibers to contract together. They are called syncytial or visceral smooth muscle, and are found in the walls of most viscera.  Contraction of smooth muscle Chemical basis for smooth muscle contraction is similar to that of the skeletal muscle (i.e it contains both actin and myosin filaments). Physical basis for smooth muscle contraction is different from that of the skeletal muscle in the following way: They do not have the same striated arrangement of actin and myosin filaments. Actin filaments are attached to the dense bodies which are attached to the cell membrane. Dense bodies of adjacent cell membranes are bonded together by intercellular protein bridges which permit transmission of contractile force from one cell to the other. There are usually 5 to 10 times as many actin filaments as myosin filaments. Comparison of smooth muscle and skeletal muscle contraction Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue. A typical smooth muscle requires a total contraction time of 1 to 3 seconds. Slow Cycling of the Myosin Cross-Bridges. Attachment of myosin cross-bridges to actin, then release from the actin, and reattachment for the next cycle— is much, much slower in smooth muscle than in skeletal muscle. Energy Required to Sustain Smooth Muscle Contraction. Only 1/10 to 1/300 as much energy is required to sustain the same tension of contraction in smooth muscle as in skeletal muscle. Force of Muscle Contraction. It is much greater in the smooth muscle than the skeletal muscle.  Control of smooth muscle contraction Unlike skeletal muscles, smooth muscles can be stimulated to contract by multiple types of signals: Nervous signals Hormonal stimulation Stretch of the muscle Change in the chemical environment of the fiber.  The vesicles of the autonomic nerve fiber endings contain acetylcholine in some fibers and norepinephrine in others, but they are never secreted by the same nerve fibers. Acetylcholine is an excitatory transmitter substance in some organs but an inhibitory transmitter in other organs. When acetylcholine excites a muscle fiber, norepinephrine ordinarily inhibits it. Conversely, when acetylcholine inhibits a fiber, norepinephrine usually excites it. Some of the receptor proteins are excitatory receptors, whereas others are inhibitory receptors. Thus, the type of receptor determines whether the smooth muscle is inhibited or excited. and also determines which of the two transmitters, acetylcholine or norepinephrine, is effective in causing the excitation or inhibition.  Membrane Potentials and Action Potentials in Smooth Muscle The intracellular potential of a smooth muscle fiber is usually about -50 to -60 millivolts. The action potentials of visceral smooth muscle (unitary smooth muscle) occur in one of two forms: (1) Spike potentials (similar to those of skeletal muscle) (2) Action potentials with plateaus. Here after the spike potential, the repolarization is delayed for several hundred to as much as 1000 milliseconds (1 second). This accounts for the prolonged contraction that occurs in some types of smooth muscle, such as ureter and uterus.  Calcium Channels Are Important in Generating the Smooth Muscle Action Potential. More voltage-gated calcium channels are present in smooth muscles but few voltage-gated sodium channels (in contrast to sk muscle). Therefore, sodium participates little in the generation of the action potential in most smooth muscle. Instead, flow of calcium ions to the interior of the fiber is mainly responsible for the action potential (the calcium channels open many times more slowly than do sodium channels, causing plateau in some smooth muscles)  Slow Wave Potentials in Unitary Smooth Muscle Can Lead to Spontaneous Generation of Action Potentials Some smooth muscle is self-excitatory—that is, action potentials arise within the smooth muscle cells without an extrinsic stimulus. This activity is often associated with a basic slow wave rhythm of the membrane potential. The slow waves are suggested to occur by waxing and waning of the pumping of positive ions (presumably sodium ions) outward through the muscle fiber membrane; that is, the membrane potential becomes more negative when sodium is pumped rapidly and less negative when the sodium pump becomes less active When the slow waves are strong enough, they can initiate action potentials. The slow waves themselves cannot cause muscle contraction. Typical spike potential Repeated spike potential elicited by slow rhythmical waves in the intestinal wall Action potential with plateau in the uterus  REGULATION OF CONTRACTION BY CALCIUM IONS An increase in intracellular calcium ions is mandatory for smooth M. contraction. This can be caused by nerve stimulation of the smooth muscle fiber, hormonal stimulation, stretch of the fiber, or even change in the chemical environment of the fiber. Sarcoplasmic reticulum is only slightly developed in most smooth muscle (unlike Sk muscles). Instead, most of the calcium ions that cause contraction enter the muscle cell from the extracellular fluid at the time of the action potential Q/What is the difference between skeletal and smooth muscles in using calcium ions for muscle contraction at the time of muscle action potential?  Smooth Muscle Contraction in Response to Local Tissue Chemical Factors: 1. Lack of oxygen in the local tissues causes smooth muscle relaxation and, therefore, vasodilatation. 2. Excess carbon dioxide causes vasodilatation. 3. Increased hydrogen ion concentration causes vasodilatation. Effects of Hormones on Smooth Muscle Contraction Most circulating hormones in the blood affect smooth muscle contraction to some degree, and some have profound effects. Among the more important of these are norepinephrine, epinephrine, acetylcholine, angiotensin, endothelin, vasopressin, oxytocin, serotonin, and histamine.