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Am J Physiol Cell Physiol 281: C1251-C1258, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 4, C1251-C1258, October 2001

cGMP-mediated inhibition of cardiac L-type Ca2+ current by a monoclonal antibody against the M2 ACh receptor

J. H. M. Nascimento1, L. Sallé2, J. Hoebeke3, J. Argibay2, and N. Peineau2

2 Laboratoire de Physiologie des Cellules Cardiaques et Vasculaires, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6542, Faculté des Sciences, Parc de Grandmont, 37200 Tours; 3 Centre National de la Recherche Scientifique Unité Prope de Recherche 9021, Institute de Biologie Moléculaire et Cellulaire, 67084 Strasbourg, France; and 1 Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21949-900 Rio de Janeiro, Brazil

The effects of a monoclonal antibody (B8E5) directed against the second extracellular loop of the muscarinic M2 receptor were studied on the L-type Ca2+ currents (ICa,L) of guinea pig ventricular myocytes using the whole cell patch-clamp technique. Similar to carbachol, B8E5 reduced the isoproterenol (ISO)-stimulated ICa,L but did not significantly affect basal ICa,L. Atropine blocked the inhibitory effect of B8E5. The electrophysiological parameters of ISO-stimulated ICa,L were not modified in presence of B8E5. Inhibition of ICa,L by B8E5 was still observed when intracellular cAMP was either enhanced by forskolin or maintained constant by using a hydrolysis-resistant cAMP analog (8-bromoadenosine 3',5'-cyclic monophosphate) or by applying the phosphodiesterase inhibitor IBMX. The effect of B8E5 was mimicked by 8-bromoguanosine 3',5'-cyclic monophosphate, a potent stimulator of cGMP-dependent protein kinase, and prevented by a selective inhibitor of nitric oxide-sensitive guanylyl cyclase {1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one}. These results indicate that the antibody B8E5 inhibits the beta -adrenergic-stimulated ICa,L through activation of the M2 muscarinic receptor and further suggest that the antibody acts not via the classical pathway of decreasing intracellular cAMP, but rather by increasing cGMP.

M2 muscarinic receptor; guanosine 3',5'-cyclic monophosphate-dependent protein kinase pathway; autoantibodies; guinea pig ventricular myocytes


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