Functional InsP3 receptors that may modulate excitation-contraction coupling in the heart

The roles of the Ca2+-mobilising messenger inositol 1,4,5-trisphosphate (InsP(3)) in heart are unclear, although many hormones activate InsP(3) production in cardiomyocytes and some of their inotropic, chronotropic and arrhythmogenic effects may be due to Ca2+ release mediated by InsP(3) receptors (InsP(3)Rs) [1-3], In the present study, we examined the expression and subcellular localisation of InsP(3)R isoforms, and Investigated their potential role in modulating excitation-contraction coupling (EC coupling). Western, PCR and InsP(3)-binding analysis indicated that both atrial and ventricular myocytes expressed mainly type II lnsP(3)Rs, with approximately sixfold higher levels of InsP(3)Rs in atrial cells. Co-immunostaining of atrial myocytes with antibodies against type II ryanodine receptors (RyRs) and type II InsP(3)Rs revealed that the latter were arranged in the subsarcolemmal space where they largely co-localised with the junctional RyRs. Stimulation of quiescent or electrically paced atrial myocytes with a membrane-permeant InsP(3) ester, which enters cells and directly activates InsP(3)Rs, caused the appearance of spontaneous Ca2+-release events. In addition, in paced cells, the InsP(3) ester evoked an increase in the amplitudes of action potential-evoked Ca2+ transients. These data indicate that atrial cardiomyocytes express functional InsP(3)Rs, and that these channels could modulate EC coupling. (C) 2000 Elsevier Science Ltd. All rights reserved.