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Muscarinic M1 acetylcholine receptors regulate the non‐quantal release of acetylcholine in the rat neuromuscular junction via NO‐dependent mechanism
Author(s) -
Malomouzh Artem I.,
Mukhtarov Marat R.,
Nikolsky Eugen E.,
Vyskočil František
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04696.x
Subject(s) - oxotremorine , muscarinic acetylcholine receptor , acetylcholine , chemistry , muscarinic acetylcholine receptor m2 , muscarinic acetylcholine receptor m4 , muscarinic acetylcholine receptor m3 , endocrinology , medicine , muscarine , muscarinic acetylcholine receptor m1 , neuromuscular junction , muscarinic agonist , nicotinic agonist , receptor , biology , biochemistry , neuroscience
Nitric oxide (NO), previously demonstrated to participate in the regulation of the resting membrane potential in skeletal muscles via muscarinic receptors, also regulates non‐quantal acetylcholine (ACh) secretion from rat motor nerve endings. Non‐quantal ACh release was estimated by the amplitude of endplate hyperpolarization (H‐effect) following a blockade of skeletal muscle post‐synaptic nicotinic receptors by (+)‐tubocurarine. The muscarinic agonists oxotremorine and muscarine lowered the H‐effect and the M1 antagonist pirenzepine prevented this effect occurring at all. Another muscarinic agonist arecaidine but‐2‐ynyl ester tosylate (ABET), which is more selective for M2 receptors than for M1 receptors and 1,1‐dimethyl‐4‐diphenylacetoxypiperidinium (DAMP), a specific antagonist of M3 cholinergic receptors had no significant effect on the H‐effect. The oxotremorine‐induced decrease in the H‐effect was calcium and calmodulin‐dependent. The decrease was negated when either NO synthase was inhibited by N G ‐nitro‐ l ‐arginine methyl ester or soluble guanylyl cyclase was inhibited by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one. The target of muscle‐derived NO is apparently nerve terminal guanylyl cyclase, because exogenous hemoglobin, acting as an NO scavenger, prevented the oxotremorine‐induced drop in the H‐effect. These results suggest that oxotremorine (and probably also non‐quantal ACh) selectively inhibit the non‐quantal secretion of ACh from motor nerve terminals acting on post‐synaptic M1 receptors coupled to Ca 2+ channels in the sarcolemma to induce sarcoplasmic Ca 2+ ‐dependent synthesis and the release of NO. It seems that a substantial part of the H‐effect can be physiologically regulated by this negative feedback loop, i.e., by NO from muscle fiber; there is apparently also Ca 2+ ‐ and calmodulin‐dependent regulation of ACh non‐quantal release in the nerve terminal itself, as calmidazolium inhibition of the calmodulin led to a doubling of the resting H‐effect.