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Mechanism of muscarinic control of the high-threshold calcium current in rabbit sino-atrial node myocytes

Pflügers Archiv European Journal of Physiology, ISSN: 0031-6768, Vol: 423, Issue: 1-2, Page: 21-27
1993
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The mechanism of the action of acetylcholine (ACh) on the L-type calcium current (I) was examined using a whole-cell voltage-clamp technique in single sino-atrial myocytes from the rabbit heart. ACh depressed basal I at concentrations in the range 0.05-10 μM, without previous β-adrenergic stimulation. The ACh-induced reduction of I was reversed by addition of atropine, indicating that muscarinic receptors mediate it. Incubation of cells with a solution containing pertussis toxin led to abolition of the ACh effect, suggesting that this effect is mediated by G proteins activated by muscarinic receptors. Dialysis of cells with protein kinase inhibitor or 5′-adenylyl imidodiphosphate, inhibitors of the cAMP-dependent protein kinase, decreased basal I by about 85% and suppressed the effect of ACh. The ACh effect was also absent in cells dialysed with a non-hydrolysable analogue of cAMP, 8-bromo-cAMP. The results suggest that, in basal conditions, a large part of the L-type calcium channels should be phosphorylated by protein kinase A stimulated by a high cAMP level correlated with a high adenylate cyclase activity. The depressing effect of ACh on I may occur via inhibition of the high basal adenylate cyclase activity leading to a decrease of cAMP-dependent protein kinase stimulation and thus to a dephosphorylation of calcium channels. © 1993 Springer-Verlag.

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