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  • M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar
  • Definition : - The chemical substance helpful for signal transmission in central nervous system &peripheral nervous system (via) the chemical synapses is neurotransmitters. Synaptic transmission is the predominant means by which neurons communicate with each other.
  • The criteria for Chemical neurotransmitter 1) found in presynaptic axon terminal. 2) enzymes necessary for synthesis are present in presynaptic neuron . 3) stimulation under physiological conditions results in release. 4) mechanism exist for rapid termination of action. 5) direct application to postsynaptic terminal mimics the activation of nerve stimulus.
  • 6) drugs that modify metabolism of the neurotransmitter should have predictable physiological effects invivo assuming that the drug is transported to the site where neurotransmitter acts. Not all neuron to neuron transmission is by neurotransmitters , gap junctions provides direct neuron to neuron electrical conduction.
  • Neurotransmitter is stored in synaptic vesicle released in response to nerve impulse & controled by calcium influx. Release of neurotransmitter is quantal event , that is a nerve impulse reaching presynaptic terminal result in release of transmitter from a fixed number of synaptic vesicle. Neurotransmitter action is terminated by metabolic degradation , reuptake , or diffusion into other cell types.
  • Class :- 1 acetylcholine Class : -2 The biogenic amines norepinephrine , epinephrine dopamine , serotonin . Class : - 3 amino acids gamma amino butyric acid (GABA) , glycine , glutamate , aspartate. Class : - 4 nitric acid (NO) carbonmonoxide ( co )
  • In addition to classical neurotransmitters many neuropetides are identified as definite or probable neurotransmitters, eg : - substance p , neurotensin , enkephalin , endorphin , histamine, vasoactive intestinal polypeptide, cholecystokinin , neuropeptide Y & somatostatin.
  • Neurotransmitters modulate the function of post synaptic cells by binding to specific receptors of 2 types 1) ionotropic receptors ( direct ion channels that open after binding of neurotransmitters. ) 2) metabotropic receptors ( interact with G proteins stimulating production of second messengers & activating protein kinases , which modulate the cellular events. )
  • G proteins couple several receptors to intra cellular signaling system , linking neuronal excitability to energy metabolism & second messenger systems. G protein binding receptors include adenosine , Ach ( muscarnic ), norepinephrine , dopamine , serotonin
  • Kinetics of ionotropic receptors are fast , (< 1 ms ) , because neurotransmitters directly alter the electrical property of the postsynaptic cell. Kinetics of metabotropic receptors functions over longer time periods. This contributes to the potential for selective & finely modulated signaling by neurotransmitters
  • The membrane of neuronal cell maintains an asymmetry of inside outside voltage , & is electrically excitable. Neuronal membranes are polarized to a potential of - 90 mV by the activity of Na+_k+ ATPase transport system.
  • Factors that control the neuroexcitability 1)voltage gated ion channels 2) neurotransmitter activated ion channels. 3)neuromodulators 4)second messenger system. The control of neuronal activity within normal limits is by the modulation of excitatory & inhibotory events simultaneously.
  • Ligand gated channels are responsible for communication between cells. Voltage gated sodium channels are involved in propagation of action potential , rapid activation is at -60mV due to opening of fast transient channels. Voltage gated potassium channels contribute to repolarization ,this regulate repeated firing of action potential by prolonging after spike repolarization.
  • Voltage dependent calcium channels trigger neurotransmitter release , at rapid activation is around -70mV. Autoantibodies to ca++ channels in motor nerve terminal leads to decreased release of Ach from nerve terminal , this is seen in eaton lambert myasthenic syndrome. Voltage gated channels determine how inhibitory & excitatory influences are integrated .
  • Acetyl choline Acetyl choline is the neurotransmitter used by all motor axons that arise from spinal cord, that is at neuromuscular junction. Junction consist of a single nerve terminal separated from post synaptic region by synaptic cleft. Motor end plate is the specialized portion of the muscle membrane involved in the junction.
  • Junctional folds are prominent they contain high density of Ach receptors. Synthesis of Ach takes place in cytosol of nerve terminal . choline acetyl transferase acetyl coA+ choline Ach + coA Ach is incorporated into membrane bound particle called synaptic vesicles. Assembly of synaptic vesicle with cell membrane resembles assembly of transport vesicle involving SNAREs.
  • Release of Ach into synaptic cleft occurs by exocytosis , which involves fusion of vesicle with presynaptic membrane. Nerve ending is depolarized by transmission of nerve impulse this opens the voltage gated Ca++ channels , permitting influx of Ca++ from synaptic cleft to nerve terminal , this Ca++ plays a role in exocytosis of Ach vesicle.
  • Approximately 200 vesicles are released into synaptic space. Each vesicle contains 10000 molecules of Ach. Ach binds Ach receptor , receptor undergoes conformational change opening the channel in the receptor that allows entry of Na+, k+ resulting in depolarization of muscle membrane.
  • Properties of Ach receptor of NMJ : nicotinic receptor (nicotine is an agonist for the receptor) a membrane glycoprotein containing 5 subunits. ( 2 subunits). only subunit binds Ach with high affinity. 2 molecules of Ach binds receptor to open the ion channel which permits Na+ , K+ the receptor is thus transmitter gated ion channel. autoantibodies to receptors are implicated in causation of myasthenia gravis
  • Snake venom bungarotoxin binds tightly to the subunit & can used to label the receptor . Formation of autoantibodies to Ach receptors in NMJ damage to receptors by autoantibodies reduction in number of receptors Episodic weekness of muscles supplied by cranial nerves
  • When the channel closes Ach dissociates & it is hydrolyzed by acetyl choline esterase. acetyl choline esterase Ach + H2O Acetate +choline Choline is recycled into nerve terminal by active transport , it can be used for synthesis of Ach.
  • The classical neurotransmitter of autonomic ganglia whether sympathetic or parasympathic is acetyl choline. 2 classes of receptors are present in autonomic nervous system. 1) nicotinic eceptors , 2) muscarnic recptors. Nicotinic receptors in autonomic ganglia are different from those on skeletal muscle.
  • Nicotinc & muscarnic receptors mediate excitatory postsynaptic potentials (EPSP) , but these potential have different time course. Stimulation of presynaptic neuron elicits a fast EPSP followed by a slow EPSP. Fast EPSP results from activation of nicotinic receptors which cause of ion channels to open.
  • Slow EPSP is mediated by activation of muscarnic receptors that inhibit the M current , a current that is produced by K+ conductance. Besides acetyl choline sympathetic preganglion neurons may release enkephalin , substance p , LHRH , neurotensin or somatostatin.
  • Neurotransmitter in parasympathetic postganglionic neurons is acetyl choline. Actions are mediated by 3 types of muscarnic receptors. 1) M1 receptor (neural ) produces slow excitation of ganglia. 2) M2 receptor (cardiac) activation slows the heart. 3) M3 receptor (glandular) , causing secretion, contraction of visceral smooth muscle , vascular relaxation.
  • Muscarnic Ach receptors act by way of inosine triphosphate system & they may also inhibit adenyl cyclase & thus decreasing cAMP synthesis. Muscarnic recptors also open or close ion channels particularly K+ or Ca++ this action occurs through G proteins. Muscarnic receptors relax smooth muscle by an effect on endothelial cells which produces nitric oxide (NO) .
  • Nitric oxide ( NO ) relaxes smooth muscles by stimulating guanylate cyclase &amp