Acetylcholine and Cholinergic Transmission

Acetylcholine (ACh) serves as a neurotransmitter not only at motor end plates (^ p. 56) and in the central nervous system, but also in the autonomic nervous system, ANS (^ p. 78ff.), where it is active

♦ in all preganglionic fibers of the ANS;

♦ in all parasympathetic postganglionic nerve endings;

♦ and in some sympathetic postganglionic nerve endings (sweat glands).

Acetylcholine synthesis. ACh is synthesized in the cytoplasm of nerve terminals, and acetyl coenzyme A (acetyl-CoA) is synthesized in mitochondria. The reaction acetyl-CoA + choline is catalyzed by choline acetyltransferase, which is synthesized in the soma and reaches the nerve terminals byaxoplasmic transport (^ p. 42). Since choline must be taken up from extracellular fluid byway of a carrier, this is the rate-limiting step of ACh synthesis.

Acetylcholine release. Vesicles on presynaptic nerve terminals empty their contents into the synaptic cleft when the cytosolic Ca2+ concentration rises in response to incoming action potentials (AP) (^ A, p. 50ff.). Epinephrine and norepinephrine can inhibit ACh release by stimulating presynaptic a2-adrenoceptors (^ p. 84). In postganglionic parasympathetic fibers, ACh blocks its own release by binding to presynaptic autoreceptors (M-receptors; see below), as shown in B.

ACh binds to postsynaptic cholinergic receptors or cholinoceptors in autonomic ganglia and organs innervated by parasympa-thetic fibers, as in the heart, smooth muscles (e.g., of the eye, bronchi, ureter, bladder, genitals, blood vessels, esophagus, and gastrointestinal tract), salivary glands, lacrimal glands, and (sympathetically innervated) sweat glands (^ p.80ff.). Cholinoceptors are ni-cotinic (N) or muscarinic (M). N-cholinocep-tors (nicotinic) can be stimulated by the alkaloid nicotine, whereas M-cholinoceptors (mus-carinic) can be stimulated by the alkaloid mushroom poison muscarine.

Nerve-specific NN-cholinoceptors on auto-nomic ganglia (^ A) differ from muscle-specific NM-cholinoceptors on motor end plates (^ p. 56) in that they are formed by different subunits. They are similar in that they are both ionotropic receptors, i.e., they act as cholinoceptors and cation channels at the same time. ACh binding leads to rapid Na+ and Ca2+ influx and in early (rapid) excitatory postsynaptic potentials (EPSP; ^ p. 50ff.), which trigger postsynaptic action potentials (AP) once they rise above threshold (^ A, left panel).

M-cholinoceptors (M]-M5) indirectly affect synaptic transmission through G-proteins (metabotropic receptors).

M1-cholinoceptors occur mainly on autonomic ganglia (^ A), CNS, and exocrine gland cells. They activate phospholipase C| (PLC|) via Gq protein in the postganglionic neuron. and inositol tris-phosphate (IP3) and diacyl-glycerol (DAG) are released as second messengers (^ p. 276) that stimulate Ca2+ influx and a late EPSP (^ A, middle panel). Synaptic signal transmission is modulated by the late EPSP as well as by co-transmitting peptides that trigger peptidergic EPSP or IPSP (^ A, right panel).

M2-cholinoceptors occur in the heart and function mainly via a Gi protein (^ p.274ff.). The Gi protein opens specific K+ channels located mainly in the sinoatrial node, atri-oventricular (AV) node, and atrial cells, thereby exerting negative chronotropic and dromotropic effects on the heart (^ B). The Gi protein also inhibits adenylate cyclase, thereby reducing Ca2+ influx (^ B).

M3-cholinoceptors occur mainly in smooth muscles. Similar to Mi-cholinoceptors (^ A, middle panel), M3-cholinoceptors trigger contractions by stimulating Ca2+ influx (^ p. 70). However, they can also induce relaxation by activating Ca2+-dependentNO synthase, e.g., in endothelial cells (^ p. 278).

Termination of ACh action is achieved by acetylcholinesterase-mediated cleavage of ACh molecules in the synaptic cleft (^ p. 56). Approximately 50% of the liberated choline is reabsorbed by presynaptic nerve endings (^ B).

Antagonists. Atropine blocks all M-cholino-ceptors, whereas pirenzepine selectively blocks M1-cholinoceptors, tubocurarine blocks NM-cholinoceptors (^ p. 56), and trimetaphan blocks NN-cholinoceptors.

A. Neurotransmission in autonomic ganglia

Presynaptic AP -

Cholinergic NN-receptor

Cholinergic NN-receptor

Mr Gq protein

Mrreceptor receptor

Peptide as a /— co-transmitter Peptide '

Mr Gq protein

Delicious Diabetic Recipes

Delicious Diabetic Recipes

This brilliant guide will teach you how to cook all those delicious recipes for people who have diabetes.

Get My Free Ebook


Post a comment