Inositol 1,4,5-trisphosphate receptors and electromechanical coupling in cardiomyocytes

The role of inositol 1,4,5-trisphosphate receptors (IP3Rs) in mediating Ca2+ mobilization in the adult heart is poorly understood. Moreover, whether these Ca2+ release channels are present and operative in human ventricular cardiomyocytes remains to be defined. IP3Rs may be activated after G?q-protein†"coupled receptor stimulation, affecting Ca2+ cycling, enhancing myocyte performance, and potentially favoring the occurrence of arrhythmic events. For this purpose, IP3R function was determined in left ventricular myocytes obtained from human hearts, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We identified that IP3Rs are expressed and operative in human left ventricular myocytes. After G?q-protein†"coupled receptor activation, Ca2+ mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca2+ transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca2+ elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the ventricular myocardium and arrhythmic events, suggesting that G?q-protein†"coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca2+ load by IP3Rs promote Ca2+ extrusion by forward-mode Na+/Ca2+ exchange, an important mechanism of arrhythmic events. In conclusion, the G?q-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias.