Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms

Intracellular Ca2+ plays an important role in the control of the heart rate through the interaction between Ca2+ release by ryanodine receptors in the sarcoplasmic reticulum (SR) and the extrusion of Ca2+ by the sodium- calcium exchanger which generates an inward current. A second type of SR Ca2+ release channel, the inositol 1,4,5-trisphosphate receptor (IP3R), can release Ca2+ from SR stores in many cell types, including cardiac myocytes. However, it is still uncertain whether IP3Rs play any functional role in regulating the heart rate. Accu- mulated evidence shows that IP3 and IP3R are involved in rhythm control in non-cardiac pacemaker tissues and in the embryonic heart. In this review we focus on intracellular Ca2+ oscillations generated by Ca2+ release from IP3R that initiates membrane depolarization and provides a common mechanism producing spontaneous activity in a range of cells with pacemaker function. Emerging new evidence also suggests that IP3/IP3Rs play a functional role in normal and diseased hearts and in cardiac rhythm control. Several membrane currents, including a store- operated Ca2+ current, might be activated by Ca2+ release from IP3Rs. IP3/IP3R may thus add another dimension to the complex regulation of heart rate.