6533b831fe1ef96bd1298bed

RESEARCH PRODUCT

Implication du récepteur 5-HT4 cardiaque humain dans la fibrillation auriculaire : rôle d’auto-anticorps dirigés contre ce récepteur ?

subject

description

The human cardiac 5-HT4 receptor was cloned in 1997. It is functional only in atrial myocytes where it is positively coupled via Gs to the adenylate cyclase, activates the cAMP-dependent protein kinase (PKA) and in consequence phosphorylates a variety of intracellular proteins implicated in excitation-contraction coupling. A number of studies suggest a role for the 5-HT4 receptor in the maintenance or elongation of atrial fibrillation. It is now accepted that certain cardiac pathologies involve auto-immune processes. Antibodies directed against the second extracellular loop of a number of cardiac G-protein linked receptors have been found. The human cardiac 5-HT4 receptor could therefore also be a target for auto-immune antibodies.The first part of this study investigated the functional effects of the rabbit polyclonal antibody (anti-G21V) against the h5-HT4 receptor expressed in the mammalian cell lines COS-7 and CHO. We found that the effects of the antibody seemed to depend upon the cell type and the density of expression of the receptor. Thus, when the receptor was expressed at high density in COS-7 and CHO cells, the antibody had an agonist-like effect in the former and no effect in the latter. When the receptor was expressed in CHO cells at low density, the antibody had an inverse-agonist-like effect.Otherwhise, our studies show for the first time the presence of auto-immune antibodies targeted against the 5-HT4 receptor in the sera of patients suffering from idiopathic paroxystic atrial fibrillation. Neither these human antibodies nor the polyclonal antibody (anti-G21V) raised in rabbit against the second extracellular loop of the 5-HT receptor, had any detectible effect upon the production of intracellular cAMP in enzymatically isolated human atrial myocytes. While previous studies from this laboratory have shown that antiG21V could inhibit activation by 5-HT of the L-type Ca2+ current in human myocytes. The difference between these results might suggest that the polyclonal antibody either activates a signalling pathway that does not involve cAMP, or operates in functional microdomains localised with the Ca2+ channels. In particular, atrial myocytes could express receptors at low density in domains around the Ca2+ channels and at high density in the rest of the sarcolemmal membrane conducing similar effects to clone 1 and 2.