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Pharmacology-1 PHL 313 Parasympathetic Nervous System Second Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Cholinergic Transmission The terminals of cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane ACh is synthesized in the cytoplasm from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT) Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs called hemicholiniums The action of the choline transporter is the rate-limiting step in ACh synthesis Cholinergic Transmission Once synthesized, ACh is transported from the cytoplasm into the vesicles by an antiporter that removes protons (carrier B). This transporter can be blocked by vesamicol (cholinergic physiological antagonist) Release of ACh is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with special proteins associated with the vesicular membrane (VAMPs) Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft The ACh vesicle release process is blocked by botulinum toxin (neurotoxic protein) through the enzymatic removal of two amino acids from one or more of the fusion proteins Cholinergic Transmission After release from the presynaptic terminal, ACh molecules may bind to and activate an ACh receptor (cholinoceptor) Eventually (and usually very rapidly), all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule AChE very efficiently splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter Most cholinergic synapses are richly supplied with AChE; the half-life of ACh in the synapse is therefore very short. AChE is also found in other tissues, e.g., red blood cells Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudocholinesterase], is found in blood plasma, liver, glia, and many other tissues Demonstration of Muscarinic and Nicotinic Actions of ACh, Dale’s Experiment A. B. C. D. Two kinds of effects produced by ACh. Ach causes a fall in BP due to arteriolar vasodilatation and slowing of the heart A larger dose of ACh also produces bradycardia, further reducing BP Atropine blocks the effect of ACh in lowering BP Still under the influence of atropine, a much larger dose of ACh produces nicotinic effects, causing a rise in BP and tachycardia due to stimulation of sympathetic ganglia ( vasoconstriction) and secretion of adrenaline Parasympathetic Nervous System, Receptors for acetylcholine (cholinergic receptors) I. Nicotinic receptors, nAChRs (the nicotinic actions of ACh are those that can be reproduced by the injection of nicotine) ---- Nicotinic receptors are ligand-gated ion channels whose activation results in a rapid increase in cellular permeability to sodium and calcium. Location: nAChRs are located ….. 1. At neuromuscular junctions of skeletal muscle (muscle type) Postsynaptic Excitatory (increases Na+ permeability) Agonists: ACh, carbachol (CCh), suxamethonium Stimulate skeletal muscle (contraction) Antagonists: tubocurarine, hexamethonium 2. On postganglionic neurons in the autonomic ganglia (ganglion type) Postsynaptic Excitatory (increases Na+ permeability) Agonists: ACh, CCh, nicotine Stimulate all autonomic ganglia Antagonists: mecamylamine, trimetaphan Parasympathetic Nervous System, Cholinergic receptors 3. On some central nervous system neurons (CNS type) Pre- and postsynaptic Excitatory (increases Na+ permeability) Agonists: nicotine, ACh Pre- and postsynaptic stimulation of many brain regions Antagonists: mecamylamine, methylaconitine 4. On adrenal medulla ACh stimulates secretion of adrenaline from adrenal medulla Parasympathetic Nervous System, Cholinergic receptors II. Muscarinic receptors, mAChRs (the muscarinic actions of ACh are those that can be reproduced by the injection of muscarine) ---- Muscarinic receptors are GPCRs: (odd-numbered members “M1, M3, M5) act through the inositol phosphate pathway, while the even-numbered receptors (M2, M4) act by inhibting adenylate cyclase, and thus reducing intracellular cAMP. mAChR also may activate or inhibit potassium channels and calcium channels. Location: mAChRs are located … in tissues innervated by postganglionic parasympathetic neurons such as On smooth muscle On cardiac muscle On gland cells See next table for details in postganglionic sympathetic neurons to sweat glands In the central nervous system Main locations Cellular response Functional response Agonists Antagonists P139 RDRM 2. G-protein-Coupled Receptors, PIP2 Gq Targets PIP2: phosphatidylinositol4,5-bisphosphate IP3: inositol-1,4,5trisphosphate DAG: 1,2-diacylglycerol