id: PW:0000841 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000841 title: acetylcholine signaling pathway description: 'Acetylcholine (ACh) is a major neurotransmitter and neuromodulator that plays important roles in the central and peripheral nervous systems, the autonomic nervous system (ANS), and also in non-neuronal cells. In cholinergic neurons acetylcholine is synthetized from acetyl-CoA and choline by the choline O-acetyltransferase Chat. The glucose-derived pyruvate metabolism is the primary source of acetyl-CoA in the brain. Once synthesized, ACh is loaded into synaptic vesicles by the vesicular ACh transporter Slc18a3, known as VACht. Upon release, ACh activates two types of receptors: the ionotropic nicotinic (nAChRs) [ click, to access the page ] and the metabotropic muscarinic (mAChRs) [ click to access the page ] receptors. The signal is rapidly terminated by the hydrolysis of ACh carried out by the acetylcholine esterase Ache; the resulting choline is up-taken by the high affinity transporter Slc5a7, known as Cht1. Ache is very fast acting enzyme and Ach clearance occurs in less than a millisecond. The ionotropic nicotinic receptors are part of the Cys-loop ligand-gated ion channel superfamily that form homo- and heteropentamers. The mAChRs are G-protein coupled receptors (GPCRs) that are subdivided into two families, depending on the type of G protein to which they couple. The two receptor types derive their names because in addition to the endogenous ACh ligand they can be activated by nicotine, an alkaloid found in tobacco and other plants and by muscarine, a natural product of certain mushrooms. In the autonomic nervous system (ANS), the part of the peripheral nervous system whose sympathetic and parasympathetic branches mediate the various responses that generally are below conscious control, referred to as visceral, ACh plays a central role. Ach is released from both the sympathetic and parasympathetic preganglions and from the parasympathetic postganglions. The ACh receptors of both sympathetic and parasympathetic postganglions are the nicotinic receptors while the muscarinic receptors are on the cell membrane of effector tissues. Most sympathetic postganglions release the norepinephrine neurotransmitter that activate adrenergic receptors on terminal effectors (not shown). Sympathetic preganglions also synapse directly on the adrenal medulla, the part of the adrenal gland whose cells are derived from the embryonic neural crest and is actually considered a ganglion of the sympathetic nervous system. However, unlike the regular sympathetic postganglions, the adrenal medulla releases hormones into the blood, rather than neurotransmitter in response to Ach. ~20% of its output is norepinephrine, the rest is epinephrine; the adrenal medulla has the methyltransferase that methylates norepinephrine to produce epinephrine. The two molecules, referred to as catecholamines, are agonists for the adrenergic receptors (not shown). The two divisions of the autonomic nervous system elicit different and opposite functions that are complementary rather than antagonistic. The sympathetic nervous system accounts for the ''fight or flight'' response while the parasympathetic accounts for the ''rest and digest'' - together, promoting the system''s homeostasis. The diagram is intended to provide an overall picture of acetylcholine function and as such does not portray the details of those autonomic responses beyond the function of ACh. In the somatic peripheral nervous system, Ach mediates muscle contraction in the skeletal muscle fiber via activation of nicotinic receptors. In the central nervous system Ach signaling via both receptor types plays important roles in hippocampal plasticity and is also involved in cognition, learning and emotion. Ach signaling is also important in development, the regulation of immune responses and in non-neuronal cells. Opening of nAChRs leads to membrane depolarization to generate firing and modulate excitability of the postsynaptic neuron while the presynaptic receptors are involved in the modulation of neurotransmitter release. The mAChRs are expressed both pre and post-synaptically. The presynaptic receptors act as inhibitory auto-receptors to control Ach release; the postsynaptic receptors exert both inhibitory and excitatory roles via activation of particular G proteins. The deregulation of acetylcholine signaling system has been associated with a range of conditions, including neurodegenerative, depression and schizophrenia and muscular disorders. Exposure to organophosphates, compounds found in pesticides and insecticides, inhibit Ache leading to uncensored activation of both nAChRs and mAChRs. In addition to addiction, nicotine in high amounts can exert harmful toxic effects.' diagram_image: https://rgd.mcw.edu/pathway/PW0000841/acetylcholine%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000841/acetylcholine%20signaling%20pathway/acetylcholine%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000842 label: acetylcholine signaling via nicotinic acetylcholine receptor - id: PW:0000843 label: acetylcholine signaling via muscarinic acetylcholine receptor diagram_gene_links: [] diagram_chemicals: - id: CHEBI:15355 label: ACh. - id: CHEBI:33568 label: epinephrine - id: CHEBI:33569 label: norepinephrine diagram_edges: - source: ACh relation: associated_with target: nAChR - source: ACh relation: associated_with target: nAChR. - source: ACh. relation: associated_with target: mAChR - source: acetylcholine signaling via muscarinic acetylcholine receptor relation: positively_affects target: effector tissues - source: acetylcholine signaling via muscarinic acetylcholine receptor relation: positively_affects target: epithelial cells - source: acetylcholine signaling via muscarinic acetylcholine receptor relation: positively_affects target: forebrain - source: acetylcholine signaling via nicotinic acetylcholine receptor relation: positively_affects target: epithelial cells - source: acetylcholine signaling via nicotinic acetylcholine receptor relation: positively_affects target: hippocampus - source: acetylcholine signaling via nicotinic acetylcholine receptor relation: positively_affects target: skeletal muscle fiber - source: adrenal medulla relation: positively_affects target: epinephrine - source: adrenal medulla relation: positively_affects target: norepinephrine - source: epinephrine relation: positively_affects target: blood - source: mAChR relation: positively_affects target: bronchoconstriction - source: mAChR relation: positively_affects target: decreased heart rate - source: norepinephrine relation: positively_affects target: blood - source: norepinephrine relation: positively_affects target: terminal structures - source: parasympathetic postganglion relation: positively_affects target: ACh. - source: parasympathetic preganglion relation: positively_affects target: ACh - source: sympathetic postganglion relation: positively_affects target: norepinephrine - source: sympathetic preganglion relation: positively_affects target: ACh diagram_labels: - acetylcholine signaling via nicotinic acetylcholine receptor --+> parasympathetic postganglion - acetylcholine signaling via nicotinic acetylcholine receptor --+> sympathetic postganglion - adrenal medulla - blood - brainstem - bronchoconstriction - decreased heart rate - effector tissues - emotion - endothelial cells - epithelial cells - forebrain - hippocampus - immune cells - learning and/or memory - mAChR - midbrain - muscle contraction - nAChR - nAChR. - pallium - parasympathetic postganglion - parasympathetic preganglion - skeletal muscle fiber - sympathetic postganglion - sympathetic preganglion - synaptic plasticity - terminal structures references: - id: RGD:8549504 citation: 'Szutowicz A, etal., Neurochem Res. 2013 Aug;38(8):1523-42. doi: 10.1007/s11064-013-1060-x. 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