Chapter 1l Cell Physiology

14 BRS Physiology One-half of the choline is taken back into the presynaptic ending by Na+-choline cotransport and used to synthesize new ACh. AChE inhibitors (neostigmine) block the degradation of ACh, prolong its action at the muscle end plate, and increase the size of the EPP. Hamicholinium blocks choline reuptake and depletes the presynaptic endings of ACh stores. B. Disease-myasthenia gravis is caused by the presence of antibodies to the ACh receptor. is characterized by skeletal muscle weakness and fatigability resulting from a reduced number of ACh receptors on the muscle end plate. The size of the EPP is reduced; therefore, it is more difficult to depolarize the muscle membrane to threshold and to produce action potentials. Treabnent with AChE inhibitors (e.g., neostigmine) prevents the degradation of ACh and prolongs the action of ACh at the muscle end plate, partially compensating for the reduced number of receptors. C. Synaptic transmission 1. Types of arrangements a. One-to-one synapses (such as those found at the neuromuscular junction) An action potential in the presynaptic element (the motor nerve) produces an action potential in the postsynaptic element (the muscle). b. Many-to-one synapses (such as those found on spinal motoneurons) An action potential in a single presynaptic cell is insufficient to produce an action potential in the postsynaptic cell. Instead, many cells synapse on the postsynaptic cell to depolarize it to threshold. The presynaptic input may be excitatory or inhibitory. 2. Input to synapses The postsynaptic cell integrates excitatory and inhibitory inputs. When the sum of the input brings the membrane potential of the postsynaptic cell to threshold, it fires an action potential. a. Excitatory postsynaptic potentials (EPSPs) are inputs that depolarize the postsynaptic cell, bringing it closer to threshold and closer to firing an action potential. are caused by opening of channels that are permeable to Na+ and 1(+, similar to the ACh channels. The membrane potential depolarizes to a value halfway between the equilibrium potentials for Na+ and K+ (approximately 0 mV). Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin. b. Inhibitory postsynaptic potentials (IPSPs) are inputs that hyperpolarize the postsynaptic cell, moving it away from threshold and farther from firing an action potential are caused by opening Cl- channels. The membrane potential is hyperpolarized toward the cl- equilibrium potential (-90 mV). Inhibitory neurotransmitters are y-aminobutyric acid (GABA) and glycine. 3. Summation at synapses a. Spatial summation occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously. Together, they produce greater depolarization. b. Temporal summation occurs when two excitatory inputs arrive at a postsynaptic neuron in rapid succession. Because the resulting postsynaptic depolarizations overlap in time, they add in stepwise fashion. c. Facilitation, augmentation, and posttetanic potentiation occur after tetanic stimulation of the presynaptic neuron. In each of these, depolarization of the postsynaptic neuron is greater than expected because greater than normal amounts of l3kt:ltlll Cell Physiology 15 neurotransmitter are released, possibly because of the accumulation of Ca2+ in the presynaptic terminal. Long-term potentiation (memory) involves new protein synthesis. 4. Neurotransmitters a. ACh (see VB) b. Norepinephrine, epinephrine, and dopamine (Figure 1.10) (1 t Norepinephrine is the primary transmitter released from postganglionic sympathetic neurons. is synthesized in the nerve terminal and released into the synapse to bind with a or I} receptors on the postsynaptic membrane. is removed from the synapse by reuptake or is metabolized in the presynaptic terminal by monoamine oxidase (MAOt and catechol-0-methyltransferase (COMTt. The metabolites are: (at 3,4-Dihydroxymandelic acid {DOMA) (b) Normetanephrine (NMN) (c) 3-Methoxy-4-hydroxyphenylglycol (MOPEG) (d) 3-Methoxy-4-hydroxymandelic acid or vanillylmandelic acid (VMA) In pheochromocytoma, a tumor of the adrenal medulla that secretes catecholamines, urinary excretion of VMA is increased. (2t Epinephrine is synthesized from norepinephrine by the action of phenylethanolamineN-methyltransferase in the adrenal medulla a methyl group is transferred to norepinephrine from S-adenosylmethionine (3t Dopamine is prominent in midbrain neurons. is released from the hypothalamus and inhibits prolactin secretion: in this context, it is called prolactin-inhibiting factor (PIF). is metabolized by MAO and COMT. (a) D, receptors activate adenylate cyclase via a G. protein. (b) 0 1 receptors inhibit adenylate cyclase via a G1 protein. (c) Parkinson disease involves degeneration of dopaminergic neurons that use the D2 receptors. (d) Schizophrenia involves increased levels of D2 receptors. Tyrosine ~ tyrosine hydroxylase L-dopa ~ dopa decarboxylase I Dopamine ~ dopamine ~-hydroxylase INorepinephrine I I l RGURE 1.10. Synthetic pathway for dopamine, norepinephrine, and epinephrine. pheny1ethanolamlne-N-methy1transferase (adrenal medulla) I Epinephrine 16 BRS Physiology c. Serotonin is present in high concentrations in the brain stem. is formed from tryptophan. is converted to melatonin in the pineal gland. d. Histamine is formed from histidine. is present in the neurons of the hypothalamus. e. Glutamate is the most prevalent excitatory neurotransmitter in the brain. There are four subtypes of glutamate receptors. Three subtypes are ionotropic receptors (ligand-gated ion channels) including the NMDA (N-methyl-o-aspartate) receptor. One subtype is a metabotropic receptor, which is coupled to ion channels via a heterotrimeric G protein. f. GABA is an inhibitory neurotransmitter. is synthesized from glutamate by glutamate decarboxylase. has two types of receptors: (1) The GABAA receptor increases CI- conductance and is the site of action of benzodiazepines and barbiturates. (2) The GABAa receptor increases K+ conductance. g. Glycine is an inhibitory neurotransmitter found primarily in the spinal cord and brain stem. increases cl- conductance. h. Nitric oxide (NO) is a short-acting inhibitory neurotransmitter in the gastrointestinal tract, blood vessels, and the central nervous system. is synthesized in presynaptic nerve terminals, where NO synthase converts arginine to citrulline and NO. is a permeant gas that diffuses from the presynaptic terminal to its target cell. also functions in signal transduction of guanylyl cyclase in a variety of tissues, including vascular smooth muscle. VI. SKELETAL MUSCLE A. Muscle structure and filaments (Figure 1.11) Each muscle fiber is multinucleate and behaves as a single unit. It contains bundles of myofibrils, surrounded by SR and invaginated by transverse tubules (T tubules). Each myofibril contains interdigitating thick and thin filaments arranged longitudinally in sarcomeres. Repeating units of sarcomeres account for the unique banding pattern in striated muscle. A sarcomere runs from Z line to Z line. 1. Thick filaments are present in the A band in the center of the sarcomere. contain myosin. a. Myosin has six polypeptide chains, including one pair of heavy chains and two pairs of light chains. b. Each myosin molecule has two "headso attached to a single "tail." The myosin heads bind ATP and actin and are involved in cross-bridge formation.