Pacemaking, arrhythmias, inotropy and hypertrophy: the many possible facets of IP3 signalling in cardiac myocytes

Abstract

Mobilization of Ca2+ from intracellular stores is a common response of many cell types to stimulation with hormones, growth factors or neurotransmitters. The ensuing increase in cytosolic Ca2+ concentration regulates numerous cellular activities. Cells express a range of channels to control the release of stored Ca2+ (Bootman et al. 2002). Of these, the best known pathways involve ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate receptors (IP3Rs). RyRs are widely, but not ubiquitously, expressed in mammalian tissues. They are particularly abundant in muscle and the brain. In cardiac muscle, RyRs generate the Ca2+ signal that allows myosin and actin filaments to interact and slide past each other, thereby triggering cellular contraction and blood pumping. The gating of RyRs is sensitive to cytosolic Ca2+ concentration. Rapid Ca2+ increases up to ∼1 μm activate the channels, whereas higher concentrations inhibit their opening. The sensitivity of RyRs to cytosolic Ca2+ allows them to act as amplifiers of cellular Ca2+ signals, a process known as ‘Ca2+-induced Ca2+ release’ (CICR). IP3Rs share structural and functional similarities to RyRs. For these channels to open, IP3 has to bind to their cytosolic face.