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Biomedical Sciences
BIOM 3200
Nicole Campbell

BIOM*3200 – Mammalian Physiology Chapter Summaries UNIT 1 – Homeostasis and Neurophysiology Pp. 4 - 8, 146 - 150, 160 – 180 Development of Pharmaceutical Drugs • Biomedical research is often aided by animal models of particular diseases. • These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. • In phase I clinical trials, the drug is tested on healthy human volunteers. • This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. • If significant toxic effects are not observed, the drug can proceed to the next stage. • In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). • Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. • Phase III trials occur in many research centers across the country to maximize the number of test participants. • At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. • If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. • Phase IV trials test other potential uses of the drug. Homeostasis and Feedback Control • Astate of relative constancy of the internal environment is known as homeostasis History of Physiology • TheAmerican physiologist Walter Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. • Cannon further suggested that the many mechanisms of physiological regulation have but one purpose— the maintenance of internal constancy. Negative Feedback Loops • When a particular measurement of the internal environment, such as a blood measurement, deviates significantly from the normal range of values, it can be concluded that homeostasis is not being maintained and that the person is sick. • In order for internal constancy to be maintained, changes in the body must stimulate sensors that can send information to an integrating center. • This allows the integrating center to detect changes from a set point. • In a similar manner, there is a set point for body temperature, blood glucose concentration, the tension on a tendon, and so on. • The integrating center is often a particular region of the brain or spinal cord, but it can also be a group of cells in an endocrine gland. • Anumber of different sensors may send information to a particular integrating center, which can then integrate this information and direct the responses of effectors—generally, muscles or glands. • The integrating center may cause increases or decreases in effector action to counter the deviations from the set point and defend homeostasis. • The thermostat of a house can serve as a simple example. Suppose you set the thermostat at a set point of 70° F. • If the temperature in the house rises sufficiently above the set point, a sensor connected to an integrating center within the thermostat will detect that deviation and turn on the air conditioner (the effector in this example). • The air conditioner will turn off when the room temperature falls and the thermostat no longer detects a deviation from the set-point temperature. • The effectors in the body are generally increased or decreased in activity, not just turned on or off. • Because of this, negative feedback control in the body works far more efficiently than does a house thermostat. • For another example, if the blood glucose con- centration falls below normal, the effectors act to increase the blood glucose. • One can think of the effectors as “defending” the set points against deviations. Because the activity of the effectors is influenced by the effects they produce, and because this regulation is in a negative, or reverse, direction, this type of control system is known as a negative feedback loop • After the air conditioner has been on for some time, the room temperature may fall significantly below the set point of the thermostat. • It is important to realize that these negative feedback loops are continuous, ongoing processes. • Thus, a particular nerve fiber that is part of an effector mechanism may always display some activity, and a particular hormone that is part of another effector mechanism may always be present in the blood. • Changes from the normal range in either direction are thus compensated for by reverse changes in effector activity. • Homeostasis is best conceived as a state of dynamic constancy in which conditions are stabilized above and below the set point. Antagonistic Effectors • Control by antagonistic effectors is sometimes described as “push-pull,” where the increasing activity of one effector is accompanied by decreasing activity of an antagonistic effector. This affords a finer degree of control than could be achieved by simply switching one effector on and off. • Normal body temperature is maintained about a set point of 37° C by the antagonistic effects of sweating, shivering, and other mechanisms. Positive Feedback • Positive feedback—in this case, the action of effectors amplifies those changes that stimulated the effectors.Athermostat that works by positive feedback, for example, would increase heat production in response to a rise in temperature. • It is clear that homeostasis must ultimately be maintained by negative rather than by positive feedback mechanisms. • The effectiveness of some negative feedback loops, however, is increased by positive feedback mechanisms that amplify the actions of a negative feedback response. Neural and Endocrine Regulation • Intrinsic, or “built into” the organs being regulated (such as molecules produced in the walls of blood vessels that cause vessel dilation or constriction); and (2) those that are extrinsic, as in regulation of an organ by the nervous and endocrine systems. • Regulation by the endocrine system is achieved by the secretion of chemical regulators called hormones into the blood, which carries the hormones to all organs in the body. • Only specific organs can respond to a particular hormone, however; these are known as the target organs of that hormone. Feedback Control and Hormone Secretion • Insulin, as previously described, produces a lowering of blood glucose. • Because a rise in blood glucose stimulates insulin secretion, a lowering of blood glucose caused by insulin’s action inhibits further insulin secretion. • This closed-loop control system is called negative feedback inhibition • The brain uses blood glucose as its primary source of energy—to entrust to the regulation of only one hormone, insulin. Pp. 146 – 150 The Membrane Potential • As a result of the permeability properties of the plasma membrane, the presence of non-diffusible + + negatively charged molecules inside the cell, and the action of the Na /K pumps, there is an unequal distribution of charges across the membrane. • This difference in charge, or potential difference, is known as the membrane potential. • Cellular proteins and the phosphate groups ofATP and other organic molecules are negatively charged at the pH of the cell cytoplasm. • These negative ions (anions) are “fixed” within the cell because they cannot penetrate the plasma membrane. + + • In this way, fixed anions within the cell influence the distribution of inorganic cations (mainly K , Na , 2+ and Ca ) between the extracellular and intracellular compartments. • Because the plasma membrane is more permeable to K than to any other cation, K accumulates within the cell more than the others as a result of its electrical attraction for the fixed anions. + • So, instead of being evenly distributed between the intracellular and extracellular compartments, K becomes more highly concentrated within the cell. + • The intracellular K concentration is 150 mEq/L in the human body compared to an extracellular concentration of 5 mEq/L (mEq = milliequivalents, which is the millimolar concentration multiplied by the valence of the ion—in this case, by one). • As a result of the unequal distribution of charges between the inside and outside of cells, each cell acts as a tiny battery with the positive pole outside the plasma membrane and the negative pole inside. • Potential difference is measured in voltage. • It is of critical importance in such physiological processes as muscle contraction, the regulation of the heartbeat, and the generation of nerve impulses. Equilibrium Potentials • The extent to which each ion contributes to the potential difference across the plasma membrane—or membrane potential—depends on (1) its concentration gradient, and (2) its membrane permeability. + • The membrane potential is usually determined primarily by the K concentration gradient. • The fixed anions would cause the intracellular K concentration to become higher than the extracellular concentration. + • If more K entered the cell because of electrical attraction, the same amount would leave the cell by net diffusion. + • Thus, a state of equilibrium would be reached where the concentrations of K remained stable. + + • The membrane potential that would stabilize the K concentrations is known as the K equilibrium potential (abbreviatedKE ). • E K is –90 millivolts (mV). • At –90 mV, these intracellular and extracellular concentrations are kept stable. + + • If this value were more negative, it would draw more K into the cell; if it were less negative, K would diffuse out of the cell. + • What would the membrane potential be if the membrane were permeable only to Na ? • This is the Na equilibrium potential abbreviated E ). • You could guess that the inside of the cell Na would have to be the positive pole, repelling the Na and causing its concentration to be lower inside than outside the cell. • The E Na is thus written as +66 mV. • Potassium equilibrium potential. If K were the only ion able to diffuse through the plasma membrane, it would distribute itself between the intracellular and extracellular compartments until an equilibrium was established.At equilibrium, the K concentration within the cell would be higher than outside the + + cell because of the attraction of K for the fixed anions. Not enough K would accumulate within the cell to neutralize these anions, however, so the inside of the cell would be – 90 millivolts compared to the outside of the cell. This membrane voltage is the equilibrium potential (E )for potassium. K • Nernst Equation o The diffusion gradient depends on the difference in concentration of the ion. o The Nernst equation allows this theoretical equilibrium potential to be calculated for a particular ion when its concentrations are known. o The following simplified form of the equation is valid at a temperature of 37° C: o View page 148 for equation. o E x equilibrium potential in millivolts (mV) for ion x o X = concentration of the ion outside the cell o o X = concentration of the ion inside the cell i + + o z = valence of the ion (+1 for Na or K ) o The equilibrium potential for a cation has a negative valui when X is greoter than X . • Resting Membrane Potential o The membrane potential of a real cell that is not producing impulses is known as the resting membrane potential. o E of +66 mV. Na + o K , its resting membrane potential would equal Khof –90 mV. o Areal resting cell is more permeable to K than to Na , but it is not completely impermeable to Na . o The actual value of the resting membrane potential de- pends on two factors:  1. The ratio of the concentratioo i(X /X ) of each ion on the two sides of the plasma membrane.  2. The specific permeability of the membrane to each different ion. + + 2+ − o Many ions—including K , Na , Ca , and Cl — contribute to the resting membrane potential.  For any given ion, a change in its concentration in the extracellular fluid will change the resting membrane potential—but only to the extent that the membrane is + permeable to that ion. Because the resting membrane is most permeable to K , a + change in the extracellular concentration of K has the greatest effect on the resting membrane potential.  Achange in the membrane permeability to any given ion will change the membrane potential. o The resting membrane potential of most cells in the body ranges from –65 mV to –85 mV (in neurons it aver- ages –70 mV). o An increased membrane permeability to Na drives the membrane potential toward (+66 Na mV) for a short time. + + Role of the Na /K Pumps + • Since the resting membrane potential is less negative than E , some K leaks out of the cell K + + • Actually, the Na /K pump does more than simply work against the ion leaks; because it transports 3 Na out of the cell for every 2 K that it moves in, it has the net effect of contributing to the negative intracellular charge • This electrogenic effect of the pumps adds approximately 3 mV to the membrane potential. + + • Of these activities, a real cell has (1) a relatively constant intracellular concentration of Na and K and (2) a constant membrane potential (in the absence of stimulation) in nerves and muscles of –65 mV to – 85 mV. + + + + • Na /K pumps produce concentration gradients for Na and K , and the presence of fixed anions and the different permeabilities of the plasma membrane to diffusible ions results in their unequal + distribution across the plasma membrane. The greater permeability of the membrane to K causes the + + membrane potential to be closer to the equilibrium potential foK K (E ) than to Na ). The resting membrane potential is different for different cells; a value of –70 mV is typical for mammalian neurons. Pp. 160 – 180 Neurons and Supporting Cells • Central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system (PNS), which includes the cranial nerves arising from the brain and the spinal nerves arising from the spinal cord. • Most neurons cannot divide by mitosis. • Supporting cells aid the functions of neurons and are about five times more abundant than neurons. • In the CNS, supporting cells are collectively called neuroglia, or simply glial cells. • Glial cells are able to divide by mitosis. Neurons • Although neurons vary considerably in size and shape, they generally have three principal regions: (1) a cell body, (2) dendrites, and (3) an axon. • Dendrites and axons can be referred to generically as processes, or extensions from the cell body. • The cell body is the enlarged portion of the neuron that contains the nucleus. It is the “nutritional center” of the neuron where macromolecules are produced. The cell body and larger dendrites (but not axons) contain Nissl bodies. • Needed for the synthesis of membrane proteins. • The cell bodies within the CNS are frequently clustered into groups called nuclei. • Cell bodies in the PNS usually occur in clusters called ganglia. • Dendrites provide a receptive area that trans- mits graded electrochemical impulses to the cell body. • The axon is a longer process that conducts impulses, called action potentials away from the cell body. • The origin of the axon near the cell body is an expanded region called the axon hillock; it is here that action potentials originate. • Side branches called axon collaterals may extend from the axon. • Special mechanisms are required to transport organelles and proteins from the cell body to the axon terminals. • This axonal transport is energy dependent and is often divided into a fast component and two slow components. The fast component (at 200 to 400 mm/day) mainly transports membranous vesicles (important for synaptic transmission). • One slow component (at 0.2 to 1 mm/day) transports microfilaments and microtubules of the cytoskeleton, while the other slow component (at 2 to 8 mm/day) transports over 200 different proteins, including those critical for synaptic function. • Axonal transport may occur from the cell body to the axon and dendrites. • This direction is called anterograde transport, and involves molecular motors of kinesin proteins that move cargo along the microtubules of the cytoskeleton. • For example, kinesin motors move synaptic vesicles, mitochondria, and ion channels from the cell body through the axon. • By contrast, axonal transport in the opposite direction— that is, along the axon and dendrites toward the cell body—is known as retrograde transport and involves molecular motor proteins of dyneins. • The dyneins move membranes, vesicles, and various molecules along microtubules of the cytoskeleton toward the cell body of the neuron. Classification of Neurons and Nerves • Sensory, or afferent, neurons conduct impulses from sensory receptors into the CNS. Motor, or efferent, neurons conduct impulses out of the CNS to effector organs (muscles and glands). • Association neurons, or interneurons, are located entirely within the CNS and serve the associative, or integrative, functions of the nervous system. • There are two types of motor neurons: somatic and autonomic. • Somatic motor neurons are responsible for both reflex and voluntary control of skeletal muscles. • Autonomic motor neurons innervate (send axons to) the involuntary effectors—smooth muscle, cardiac muscle, and glands. • There are two subdivisions of autonomic neurons: sympathetic and parasympathetic. • Autonomic motor neurons, together with their central control centers, constitute the autonomic nervous system • Pseudounipolar neurons have a single short process that branches like a T to form a pair of longer processes. • They are called pseudounipolar (from the Late Latin pseudo = false) because, although they originate with two processes, during early embryonic development their two processes converge and partially fuse. • Sensory neurons are pseudounipolar—one of the branched processes receives sensory stimuli and produces nerve impulses; the other delivers these impulses to synapses within the brain or spinal cord. • Bipolar neurons have two processes, one at either end; this type is found in the retina of the eye. • Multipolar neurons, the most common type, have several dendrites and one axon extending from the cell body; motor neurons are good examples of this type. • Anerve is a bundle of axons located outside the CNS. • Most nerves are composed of both motor and sensory fibers and are thus called mixed nerves. • Abundle of axons in the CNS are called a tract. Supporting Cells • Most of the supporting cells of the nervous system are derived from the same embryonic tissue layer (ectoderm) that produces neurons. • The term neuroglia (or glia) traditionally refers to the supporting cells of the CNS, but in current usage the supporting cells of the PNS are often also called glial cells. • There are two types of supporting cells in the peripheral nervous system: • Schwann cells (also called neurolemmocytes), which form myelin sheaths around peripheral axons; and • Satellite cells, or ganglionic gliocytes, which support neuron cell bodies within the ganglia of the PNS. There are four types of supporting cells in the central nervous system: • 0ligodendrocytes, which form myelin sheaths around axons of the CNS; • Microglia, which migrate through the CNS and phagocytose foreign and degenerated material. • Astrocytes, which help to regulate the external environment of neurons in the CNS. • Ependymal cells, which line the ventricles (cavities) of the brain and the central canal of the spinal cord. Neurilemma and Myelin Sheath • All axons in the PNS (myelinated and unmyelinated) are surrounded by a continuous living sheath of Schwann cells, known as the neurilemma, or sheath of Schwann. • The axons of the CNS, by contrast, lack a neurilemma (Schwann cells are found only in the PNS). • Some axons in the PNS and CNS are surrounded by a myelin sheath. • In the PNS, this insulating covering is formed by successive wrappings of the cell membrane of Schwann cells; in the CNS, it is formed by oligodendrocytes. • Myelin Sheath in PNS o Each Schwann cell wraps only about a millimeter of axon, leaving gaps of exposed axon between the adjacent Schwann cells. o These gaps in the myelin sheath are known as the nodes of Ranvier. • Myelin Sheath in CNS o The myelin sheaths around axons of the CNS give this tissue a white color; areas of the CNS that contain a high concentration of axons thus form the white matter. o The gray matter of the CNS is composed of high concentrations of cell bodies and dendrites, which lack myelin sheaths. • Regeneration of a CutAxon o When an axon in a peripheral nerve is cut, the distal portion of the axon that was severed from the cell body degenerates and is phagocytosed by Schwann cells. o The Schwann cells, surrounded by the basement membrane, then form a regeneration tube as the part of the axon that is connected to the cell body begins to grow and exhibit amoeboid movement. • Neurotrophins o In a developing fetal brain, chemicals called neurotrophins promote neuron growth. Nerve growth factor (NGF) was the first neurotrophins. o In a developing fetal brain, chemicals called neurotrophins promote neuron growth. Nerve growth factor (NGF) was the first neurotrophins. o NGF is required for the maintenance of sympathetic ganglia, and there is evidence that neurotrophins are required for mature sensory neurons to regenerate after injury. Functions ofAstrocytes • Astrocytes (from the Greek aster = star) are large stellate cells with numerous cytoplasmic processes that radiate outward. • They are the most abundant of the glial cells in the CNS, constituting up to 90% of the nervous tissue in some areas of the brain. • Blood-Brain Barrier o Unlike other organs, therefore, the brain cannot obtain molecules from the blood plasma by a nonspecific filtering process. o Instead, molecules within brain capillaries must be moved through the endothelial cells by diffusion and active transport, as well as by endocytosis and exocytosis. o This feature of brain capillaries imposes a very selective blood-brain barrier. ElectricalActivity inAxons • The permeability of the axon membrane to Na and K depends on gated channels that open in response to stimulation. + + • Net diffusion of these ions occurs in two stages: first Na moves into the axon, and then K moves out. • This flow of ions, and the changes in the membrane potential that result, constitute an event called an action potential. • All cells in the body maintain a potential difference (voltage) across the membrane, or resting membrane potential (rmp), in which the inside of the cell is negatively charged in comparison to the outside of the cell (for example, in neurons it is −70 mV). • The action of the Na /K pumps also helps to maintain a potential difference because they pump out 3 sodium ions (Na ) for every 2 potassium ions (K ) that they transport into the cell. • Partly as a result of these pumps, Na is more highly concentrated in the extracellular fluid than inside + the cell, whereas K is more highly concentrated within the cell. • Neurons maintain an average rmp of −70 mV, for example, whereas heart muscle cells may have an rmp of −85 mV. • If appropriate stimulation causes positive charges to flow into the cell, the line will deflect upward. • This change is called depolarization (or hypopolarization) because the potential difference between the two recording electrodes is reduced. • Areturn to the resting membrane potential is known as repolarization. • If stimulation causes the inside of the cell to become more negative than the resting membrane potential, the line on the oscilloscope will deflect downward. • This change is called hyperpolarization. • Hyper- polarization can be caused either by positive charges leaving the cell or by negative charges entering the cell. • Depolarization of a dendrite or cell body is excitatory, whereas hyperpolarization is inhibitory Ion Gating InAxons + + • Ions such as Na , K , and others pass through ion channels in the plasma membrane that are said to be gated channels. • The “gates” are part of the proteins that compose the channels, and can open or close the ion channels in response to particular stimuli. • When ion channels are closed, the plasma membrane is less permeable, and when the channels are open, the membrane is more permeable to an ion. + + • The ion channels for Na and K are specific for each ion. • There are two types of channels for K . • One type is gated, and the gates are closed at the resting membrane potential. The other type is not + gated; these K channels are thus always open and are often called leakage channels. • Channels for Na , by contrast, are all gated and the gates are closed at the resting membrane potential. • However, the gates of closed Na channels appear to flicker open (and quickly close) occasionally, allowing some Na to leak into the resting cell. + • Because the inside of the cell is negatively charged relative to the outside, and the concentration of Na is lower inside of the cell, the electrochemical gradient (the combined electrical and concentration + + gradients) for Na causes Na to rush into the cell. • This causes the membrane potential to move rapidly toward the sodium equilibrium potential • Because opening of the gated Na and K channels is stimulated by depolarization, these ion channels in the axon membrane are said to be voltage-regulated, or voltage-gated, channels. • The channel gates are closed at the resting membrane potential of −70 mV and open in response to depolarization of the membrane to a threshold value. Action Potentials • When the axon membrane has been depolarized to a threshold level—in the previous example, by + + stimulating electrodes—the Na gates open and the membrane becomes permeable to Na . + • This permits Na to enter the axon by diffusion, which further depolarizes the membrane (makes the inside less negative, or more positive). + • The gates for the Na channels of the axon membrane are voltage regulated, and so this additional + + depolarization opens more Na channels and makes the membrane even more permeable to Na . + • As a result, more Na can enter the cell and induce a depolarization that opens even more voltage- + + regulated Na gates.Apositive feedback loop (fig. 7.13) is thus created, causing the rate of Na entry and depolarization to accelerate in an explosive fashion. • The explosive increase in Na permeability results in a rapid reversal of the membrane potential in that region from −70 mV to +30 mV. + • At that point the channels for Na close (they actually become inactivated, causing a rapid decrease in Na permeability • Because K is positively charged, the diffusion of K out of the cell makes the inside of the cell less positive, or more negative, and acts to restore the original resting membrane potential of −70 mV. • This process is called repolarization and represents the completion of a negative feedback loop (fig. 7.13). + + • These changes in Na and K diffusion and the resulting changes in the membrane potential they produce constitute an event called the action potential, or nerve impulse. + + • As the Na channels are becoming inactivated, the gated K channels open and the membrane potential + moves toward the K equilibrium potential. • This outward diffusion of K repolarizes the membrane. • Actually, the membrane potential slightly overshoots the resting membrane potential, producing an + after-hyperpolarization as a result of the continued outward movement of K . • However, the gated K channels close before this after-hyperpolarization can reach the K equilibrium potential (−90 mV). • Then the after-hyper-polarization decays, and the resting membrane potential is reestablished. • All-or-None Law o The amplitude (size) of action potentials is therefore all or none. o When depolarization is below a threshold value, the voltage-regulated gates are closed; when depolarization reaches threshold, a maximum potential change (the action potential) is produced. o Because the change from −70 mV to +30 mV and back to −70 mV lasts only about 3 msec, the image of an action potential on an oscilloscope screen looks like a spike. o Action potentials are therefore sometimes called spike potentials. o The channels are open only for a fixed period of time because they are soon inactivated, a process different from simply closing the gates. o Inactivation occurs automatically and lasts until the membrane has repolarized. o Because of this automatic inactivation, all action potentials have about the same duration. • Refractory Periods o During the time that a patch of axon membrane is producing an action potential, it is incapable of responding— is refractory—to further stimulation. o If a second stimulus is applied during most of the time that an action potential is being produced, the second stimulus will have no effect on the axon membrane. o The membrane is thus said to be in an absolute refractory period; it cannot respond to any subsequent stimulus. o Thus, during the time that the Na channels are in the process of recovering from their inactivated state and the K channels are still open, the membrane is said to be in a relative refractory period. o Because the cell membrane is refractory when it is producing an action potential, each action potential remains a separate, all-or-none event. • Cable Properties of Neurons o The cable properties of neurons are their abilities to conduct charges through their cytoplasm. o If an axon had to conduct only through its cable properties, therefore, no axon could be more than a millimeter in length. o The fact that some axons are a meter or more in length suggests that the conduction of nerve impulses does not rely on the cable properties of the axon. Conduction of Nerve Impulses • Conduction in an UnmyelinatedAxon + + o In an unmyelinated axon, every patch of membrane that contains Na and K channels can produce an action potential. o Action potentials are thus produced along the entire length of the axon. o The action potential produced at the last region of the axon has the same amplitude as the action potential produced at the first region. o Action potentials are thus said to be conducted without decrement (without decreasing in amplitude). o Thus, the more action potentials along a given stretch of axon that have to be produced, the slower the conduction. o Because action potentials must be produced at every fraction of a micrometer in an unmyelinated axon, the conduction rate is relatively slow. o This conduction rate is somewhat faster if the unmyelinated axon is thicker, because thicker axons have less resistance to the flow of charges (so conduction of charges by cable properties is faster). o The conduction rate is substantially faster if the axon is myelinated, because fewer action potentials are produced along a given length of myelinated axon. • Conduction in a Myelinated Axon + + o The myelin sheath provides insulation for the axon, preventing movements of Na and K through the membrane. o The myelin thus has interruptions— the nodes of Ranvier o Because the cable properties of axons can conduct depolarizations over only a very short distance (1 to 2 mm), the nodes of Ranvier cannot be separated by more than this distance. o Action potentials, therefore, occur only at the nodes of Ranvier (fig. 7.20) and seem to “leap” from node to node—a process called saltatory conduction (from the Latin saltario = leap). o Myelinated axons conduct the action potential faster than unmyelinated axons. o This is because myelinated axons have voltage-gated channels only at the nodes of Ranvier, which are about 1 mm apart, whereas unmyelinated axons have these channels along their entire length. The Synapse • Axons end close to, or in some cases at the point of con- tact with, another cell. • Once action potentials reach the end of an axon, they directly or indirectly stimulate (or inhibit) the other cell. • In specialized cases, action potentials can directly pass from one cell to another. • In most cases, however, the action potentials stop at the axon terminal, where they stimulate the release of a chemical neurotransmitter that affects the next cell. • Asynapse is the functional connection between a neuron and a second cell. In the CNS, this other cell is also a neuron. In the PNS, the other cell may be either a neuron or an effector cell within a muscle or gland. • The latter synapses are often called myoneural, or neuromuscular, junctions. • In almost all synapses, transmission is in one direction only—from the axon of the first (or presynaptic) neuron to the second (or postsynaptic) neuron. • Most commonly, the synapse occurs between the axon of the presynaptic neuron and the dendrites and cell body of the postsynaptic neuron. • This led to the hypothesis that synaptic transmission might be chemical—that the presynaptic nerve endings might release chemicals called neurotransmitters that stimulated action potentials in the postsynaptic cells. • Loewi concluded that the nerve endings of the vagus must have released a chemical—which he called Vagusstoff— that inhibited the heart rate. • This chemical was subsequently identified as acetylcholine, or ACh. Electrical Synapses: Gap Junctions • In order for two cells to be electrically coupled, they must be approximately equal in size and they must be joined by areas of contact with low electrical resistance. • In this way, impulses can be regenerated from one cell to the next with- out interruption.Adjacent cells that are electrically coupled are joined together by gap junctions. • In gap junctions, the membranes of the two cells are separated by only 2 nano-meters (1 nano meter = −9 10 meter). Chemical Synapses • Transmission across the majority of synapses in the nervous system is one-way and occurs through the release of chemical neurotransmitters from presynaptic axon endings. • These presynaptic endings, called terminal boutons (from the Middle French bouton = button) because of their swollen appearance, are separated from the postsynaptic cell by a synaptic cleft so narrow (about 10 nm) that it can be seen clearly only with an electron microscope • Chemical transmission requires that the synaptic cleft stay very narrow and that neurotransmitter molecules are released near their receptor proteins in the postsynaptic membrane. • Cell adhesion molecules (CAMs) are proteins in the pre- and postsynaptic membranes that project from these membranes into the synaptic cleft, where they bond to each other. • This Velcro-like effect ensures that the pre- and postsynaptic membranes stay in close proximity for rapid chemical transmission. UNIT 2 Pp. 180-191 • Release of Neurotransmitter o Neurotransmitter molecules within the presynaptic neuron endings are contained within many small, membrane-enclosed synaptic vesicles. • Action of Neurotransmitter o Once the neurotransmitter molecules have been released from the presynaptic axon terminals, they diffuse rapidly across the synaptic cleft and reach the membrane of the postsynaptic cell. o The neurotransmitters then bind to specific receptor proteins that are part of the postsynaptic membrane. o The term ligand in this case refers to a smaller molecule (the neurotransmitter) that binds to and forms a complex with a larger protein molecule (the receptor). o Binding of the neurotransmitter ligand to its receptor protein causes ion channels to open in the postsynaptic membrane. o The gates that regulate these channels, therefore, can be called chemically regulated (or ligand-regulated) gates because they open in response to the binding of a chemical ligand to its receptor in the postsynaptic plasma membrane. o Voltage-regulated channels are found primarily in the axons; chemically regulated channels are found in the postsynaptic membrane. o Voltage-regulated channels open in response to depolarization; chemically regulated channels open in response to the binding of postsynaptic receptor proteins to their neurotransmitter ligands. o When the chemically regulated ion channels are opened, they produce a graded change in the membrane potential, also known as a graded potential. o This depolarization is called an excitatory postsynaptic potential (EPSP) because the membrane potential moves toward the threshold required for action potentials. o This hyperpolarization is called an inhibitory postsynaptic potential (IPSP) because the membrane potential moves farther from the threshold depolarization required to produce action potentials. o Excitatory postsynaptic potentials, as their name implies, stimulate the postsynaptic cell to produce action potentials, and inhibitory postsynaptic potentials antagonize this effect. o The total depolarization produced by the summation of EPSPs and IPSPs at the initial segment of the axon will determine whether the axon will fire action potentials, and the frequency with which it fires action potentials. Acetylcholine as a Neurotransmitter • Acetylcholine (ACh) is used as an excitatory neurotransmitter by some neurons in the CNS and by somatic motor neurons at the neuromuscular junction. • At autonomic nerve endings,ACh may be either excitatory or inhibitory, depending on the organ involved. • The stimulatory effect ofACh on skeletal muscle cells is produced by the binding ofACh to nicotinicACh receptors, so named because they can also be activated by nicotine. • Effects ofACh on other cells occur whenACh binds to muscarinicACh receptors; these effects can also be produced by muscarine (a drug derived from certain poisonous mushrooms). • 1. Nicotinic ACh receptors. These are found in specific regions of the brain (chapter 8), in autonomic ganglia (chapter 9), and in skeletal muscle fibers (chapter 12). The release ofACh from somatic motor neurons and its subsequent binding to nicotinic receptors, for example, stimulates muscle contraction. • 2. Muscarinic ACh receptors. These are found in the plasma membrane of smooth muscle cells, cardiac muscle cells, and the cells of particular glands (chapter 9). Thus, the activation of muscarinicACh receptors byACh released from autonomic axons is required for the regulation of the cardiovascular system (chapter 14), digestive system (chapter 18), and others. Muscarinic ACh receptors are also found in the brain. • Drugs that activate receptor proteins are called agonists, and drugs that inhibit receptor proteins are antagonists. Chemically Regulated Channels • The binding of a neurotransmitter to its receptor protein can cause the opening of ion channels through two different mechanisms. • Ligand-Gated Channels o A neurotransmitter molecule is the ligand that binds to its specific receptor protein. o For ion channels that are “ligand-gated,” the receptor protein is also an ion channel; these are two functions of the same protein. o When the neurotransmitter ligand binds to its membrane receptor, a central ion channel opens through the same receptor/channel protein. o The nicotinicACh receptor can serve as an example of ligand-gated channels. o Two of its five-polypeptide subunits containACh-binding sites, and the channel opens when both sites bind toACh (fig. 7.26). o The opening of this channel permits the simultaneous diffusion of Na into and K out of the postsynaptic cell. • G-Protein-Coupled Channels o This group of channels differs from ligand-gated channels in that the receptors and the ion channels are different, separate membrane proteins. o Thus, binding of the neurotransmitter ligand to its receptor can open the ion channel only indirectly. o Unlike the nicotinic receptors, these receptors do not contain ion channels. o The ion channels are separate proteins located at some distance from the muscarinic receptors. • There are three G-protein subunits, designated alpha, beta, and gamma. o In response to the binding ofACh to its receptor, the alpha subunit dissociates from the other two subunits, which stick together to form a beta-gamma complex. o MuscarinicACh receptors require the action of G-proteins. o The figure depicts the effects ofACh on the pacemaker cells of the heart. o Binding ofACh to its muscarinic receptor causes the beta-gamma subunits to dissociate from the alpha subunit. o The beta-gamma complex of G-proteins then binds to a K channel, causing it to open. o Outward diffusion of K results, slowing the heart rate. Acetylcholinesterase (AChE) • The inactivation ofACh is achieved by means of an enzyme called acetylcholinesterase, or AChE, which is present on the postsynaptic membrane or immediately outside the membrane, with its active site facing the synaptic cleft Acetylcholine in the PNS • Somatic motor neurons form synapses with skeletal muscle cells (muscle fibers). • At these synapses, or neuromuscular junctions, the postsynaptic membrane of the muscle fiber is known as a motor end plate. • Therefore, the EPSPs produced byACh in skeletal muscle fibers are often called end-plate potentials. • This conduction is analogous to conduction of action potentials by axons; it is significant because action potentials produced by muscle fibers stimulate muscle contraction • There are two classifications of autonomic nerves: sympathetic and parasympathetic. • Most of the parasympathetic axons that innervate the effector organs useACh as their neurotransmitter. Acetylcholine in the CNS • There are many cholinergic neurons (those that useACh as a neurotransmitter) in the CNS, where the axon terminals of one neuron typically synapse with the dendrites or cell body of another. • The dendrites and cell body thus serve as the receptive area of the neuron, and it is in these regions that receptor proteins for neurotransmitters and chemically regulated gated channels are located. • Depolarizations—EPSPs—in the dendrites and cell body spread by cable properties (see fig. 7.18) to the initial segment of the axon in order to stimulate action potentials. • If the depolarization is at or above threshold by the time it reaches the initial segment of the axon, the EPSP will stimulate the production of action potentials, which can then regenerate themselves along the axon. • If, however, the EPSP is below threshold at the initial segment, no action potentials will be produced in the postsynaptic cell Monoamines as Neurotransmitters • Among these are the monoamines, a chemical family that includes dopamine, norepinephrine, and serotonin. • Monoamines are regulatory molecules derived from amino acids. Dopamine, norepinephrine (noradrenalin), and epinephrine (adrenalin) are derived from the amino acid tyrosine and placed in a subfamily of monoamines called catecholamines. • The term catechol refers to a common six-carbon ring structure. • Other monoamines are derived from different amino acids and so are not classified as catecholamines. • Serotonin is derived from the amino acid tryptophan and functions as an important neurotransmitter. • The action of monoamine neurotransmitters at the synapse is stopped by (1) reuptake of the neurotransmitter molecules from the synaptic cleft into the presynaptic axon terminal, and then (2) degradation of the monoamine by an enzyme within the axon terminal called monoamine oxidase (MAO). • Most of the monoamine neurotransmitters, including dopamine, norepinephrine, and serotonin, are transported back into the presynaptic axon terminals after being released into the synaptic gap. They are then degraded and inactivated by an enzyme, monoamine oxidase (MAO). • The monoamine neurotransmitters do not directly cause opening of ion channels in the postsynaptic membrane. • Instead, these neurotransmitters act by means of an intermediate regulator, known as a second messenger. • In the case of some synapses that use catecholamines for syn- aptic transmission, this second messenger is a compound known as cyclic adenosine monophosphate (cAMP). • Serotonin should influence mood and emotion. • This suspicion is confirmed by the actions of the antidepressant drugs Prozac, Paxil, Zoloft, and Luvox, which act as serotonin-specific reuptake inhibitors (SSRIs). • By blocking the reuptake of serotonin into presynaptic endings, and thereby increasing the effectiveness of serotonin transmission at synapses, these drugs have proven effective in the treatment of depression. • Norepinephrine action requires G-proteins. • The binding of norepinephrine to its receptor causes the dissociation of G-proteins. • Binding of the alpha G-protein subunit to the enzyme adenylate cyclase activates this enzyme, leading to the production of cyclicAMP. CyclicAMP, in turn, activates protein kinase, which can open ion channels and produce other effects. Dopamine as a Neurotransmitter • Neurons that use dopamine as a neurotransmitter are called dopaminergic neurons. • Nigrostriatal Dopamine System o The cell bodies of the nigrostriatal dopamine system are located in a part of the midbrain called the substantia nigra (“dark substance”) because it contains melanin pigment. o Parkinson’s disease is caused by degeneration of the dopaminergic neurons in the substantia nigra. • Mesolimbic Dopamine System o The mesolimbic dopamine system involves neurons that originate in the midbrain and send axons to structures in the forebrain that are part of the limbic system (see fig. 8.21). o The dopamine released by these neurons may be involved in behavior and reward. Norepinephrine as a Neurotransmitter • Norepinephrine, likeACh, is used as a neurotransmitter in both the PNS and the CNS. • Sympathetic neurons of the PNS use norepinephrine as a neurotransmitter at their synapse with smooth muscles, cardiac muscles, and glands. Pp. 196 – 198 Nitric Oxide and Carbon Monoxide as Neurotransmitters • In addition to nitric oxide, another gas—carbon monoxide (CO)—may function as a neurotransmitter. • Certain neurons, including those of the cerebellum and olfactory epithelium, have been shown to produce carbon monoxide ATP andAdenosine as Neurotransmitters • Adenosine triphosphate (ATP) and adenosine are classified chemically as purines (chapter 2) and have multiple cellular functions. • The plasma membrane is impermeable to organic molecules with phosphate groups, trapping ATP inside cells to serve as the universal energy carrier of cell metabolism. • However, neurons and astrocytes can releaseATP by exocytosis of synaptic vesicles, and this extracellularATP, as well as adenosine produced from it by an extracellular enzyme, can function as neurotransmitters. • Purinergic receptors, designated P1 (forATP) and P2 (for adenosine), are found in neurons and glial cells and have been implicated in a variety of physiological and pathological processes. • Through the activation of different subtypes of purinergic receptors,ATP and adenosine (produced from extra- cellularATPby enzymes on the outer surface of tissue cells) serve as neurotransmitters when released as cotransmitters by neurons. • Examples in the PNS includeATP released with norepinephrine in the stimulation of blood vessel constriction and withACh in the stimulation of intestinal contractions. Synaptic Integration • Because axons can have collateral branches (see fig. 7.1), divergence of neural pathways can occur. • That is, one neuron can make synapses with a number of other neurons, and by that means either stimulate or inhibit them. • By contrast, a number of axons can synapse on a single neuron, allowing convergence of neural pathways. • Figure 7.33 shows convergence of two neurons on a single postsynaptic neuron, which can thereby integrate the input of the presynaptic neurons. • Spatial summation occurs as a result of the convergence of presynaptic axon terminals (up to a thousand in some cases) on the dendrites and cell body of a postsynaptic neuron. • Synaptic potentials, unlike action potentials, are graded and lack refractory periods; this allows them to summate, or add together, as they are conducted by the postsynaptic neuron (fig. 7.33). • In temporal summation, the successive activity of a presynaptic axon terminal causes successive waves of transmitter release, resulting in the summation of EPSPs in the postsynaptic neuron. • The summation of EPSPs helps to determine if the depolarization that reaches the axon hillock will be of sufficient magnitude to generate new action potentials in the postsynaptic neuron. • Long-term depression (LTD) is a related process in which glutamate-releasing presynaptic neurons stimulate their postsynaptic neurons to release endo-cannabinoids. • The endo-cannabinoids then act as retrograde neurotransmitters, suppressing the release of neurotransmitters from presynaptic axons that provide either excitatory or inhibitory synapses with the postsynaptic neuron. • A shorter-term form of this is depolarization-induced suppression of inhibition (DSI). • In DSI, the depolarization of a postsynaptic neuron by excitatory input suppresses (via endo- cannabinoids as retrograde neurotransmitters) the release of GABA from inhibitory presynaptic axons for 20 to 40 seconds. Synaptic Inhibition • Hyperpolarizations produced by neurotransmitters are there- fore called inhibitory postsynaptic potentials (IPSPs), as previously described. The inhibition produced in this way is called postsynaptic inhibition. • Postsynaptic inhibition in the brain is produced by GABA; in the spinal cord it is mainly produced by glycine (although GABA is also involved). • In presynaptic inhibition, the amount of an excitatory neurotransmitter released at the end of an axon is decreased by the effects of a second neuron, whose axon makes a synapse with the axon of the first neuron (an axoaxonic synapse). Pp. 356 – 372 Skeletal Muscles • Skeletal muscles are composed of individual muscle fibers that contract when stimulated by a somatic motor neuron. • Skeletal muscles are usually attached to bone on each end by tough connective tissue tendons. • When a muscle contracts, it places tension on its tendons and attached bones. • The more movable bony attachment of the muscle, known as its insertion, is pulled toward its less movable attachment known as its origin. • When flexor muscles contract, for example, they decrease the angle of a joint. • Contraction of extensor muscles increases the angle of their attached bones at the joint. • The prime mover of any skeletal movement is called the agonist muscle; in flexion, for example, the flexor is the agonist muscle. • Flexors and extensors that act on the same joint to produce opposite actions are antagonistic muscles. Structure of Skeletal Muscles • The fibrous connective tissue proteins within the tendons extend around the muscle in an irregular arrangement, forming a sheath known as the epimysium. • Dissection of a muscle fascicle under a microscope reveals that it, in turn, is composed of many muscle fibers, or myofibers. • Each is surrounded by a plasma membrane, or sarcolemma, enveloped by a thin connective tissue layer called an endomysium • The most distinctive feature of skeletal muscle fibers, however, is their striated appearance when viewed microscopically (fig. 12.2). • The striations (stripes) are produced by alternating dark and light bands that appear to span the width of the fiber. • The dark bands are called Abands, and the light bands are called I bands. At high magnification in an electron microscope, thin dark lines can be seen in the middle of the I bands. These are called Z lines (see fig. 12.6). • The letters A and I stand for anisotropic and isotropic, respectively, which indicate the behavior of polarized light as it passes through these regions; the letter Z comes from the German word Zwischenscheibe, which translates to “between disc.” Motor Units • The specialized region of the sarcolemma of the muscle fiber at the neuromuscular junction is known as a motor end plate. • Each somatic motor neuron, together with all of the muscle fibers that it innervates, is known as a motor unit (fig. 12.4). • Whenever a somatic motor neuron is activated, all of the muscle fibers that it innervates are stimulated to contract. • In vivo, graded contractions (where contraction strength is varied) of whole muscles are produced by variations in the number of motor units that are activated. • Aneuron that innervates fewer muscle fibers has a smaller cell body and is stimulated by lower levels of excitatory input than a larger neuron that innervates a greater number of muscle fibers. Mechanisms of Contraction • TheAbands within each muscle fiber are composed of thick filaments and the I bands contain thin filaments. • When muscle cells are viewed in the electron microscope, which can produce images at several thousand times the magnification possible in an ordinary light microscope, each cell is seen to be composed of many subunits known as myofibrils (fibrils = little fibers) • Each myofibril contains even smaller structures called myofilaments. • When a myofibril is observed at high magnification in longitudinal section (side view), theA bands are seen to contain thick filaments. • It is these thick filaments that give theAband its dark appearance. • The lighter I band, by contrast, contains thin filaments (from 50 to 60 Å thick). • The thick filaments are primarily composed of the protein myosin, and the th
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