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

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.

IP₃Rs are more widely expressed than RyRs, and in most tissues it is quite simple to find an extracellular agonist that will cause an IP₃-dependent increase of cytosolic Ca²⁺. Furthermore, it is generally quite obvious what Ca²⁺-dependent processes are controlled by IP₃Rs. The situation in cardiac myocytes is less clear. There is no doubt that IP₃Rs are present in cardiac myocytes. Many different laboratories have identified IP₃R mRNA transcripts, protein expression or specific IP₃ binding sites. Furthermore they have been purified and shown to form channels when re-incorporated into lipid bilayers (Perez et al. 1997). However, their precise functional roles have been enigmatic.

An obvious function for cardiac IP₃Rs is to generate Ca²⁺ signals that are spatially discrete from those occurring during excitation–contraction coupling. Indeed, it has been demonstrated that a pool of IP₃Rs located within, or close to, the nucleus can specifically regulate DNA modifying enzymes involved in controlling hypertrophic growth of cardiac myocytes (Wu et al. 2006). An additional role of IP₃Rs in cardiac myocytes would be to amplify the Ca²⁺ signal that occurs during excitation–contraction coupling. The Ca²⁺ flux through IP₃Rs could synergise with that arising from RyRs, resulting in a greater cytosolic Ca²⁺ change and stronger contraction (positive inotropy). Consistent with this notion, direct stimulation of IP₃Rs in cardiac myocytes had a positive inotropic effect in atrial and ventricular cells (Proven et al. 2006). Furthermore, myocytes from mice lacking expression of cardiac IP₃Rs did not show a positive inotropic response when stimulated with endothelin-1 (Li et al. 2005). Augmenting cardiac Ca²⁺ signalling could be a beneficial consequence of IP₃R expression. However, in many situations IP₃R-mediated inotropy develops simultaneously with the generation of spontaneous Ca²⁺ signals, which can cause arrhythmic depolarization of cardiac myocytes. In fact, the most commonly reported consequence of IP₃R activation in adult cardiac myocytes is arrhythmias (Woodcock & Matkovich, 2005). If they occur in the vicinity of the sarcolemma (the cardiac myocyte plasma membrane), spontaneous Ca²⁺ signals can stimulate depolarizing ion conductances (such as Na⁺/Ca²⁺ exchange). Since IP₃Rs are expressed at ∼100-fold lower levels than RyRs, it is perhaps surprising that they can trigger sufficient Ca²⁺ release to significantly depolarize a cell. However, IP₃Rs can be surrounded by RyRs and act as initiators of CICR to promote a regenerative release of Ca²⁺. If the Ca²⁺ signal develops sufficiently and impacts on an adequate area of sarcolemma, it will trigger a spontaneous action potential.

A further potential function for IP₃Rs is during development of cardiac myocytes. It has been demonstrated that IP₃R expression occurs before the appearance of RyRs in the early embryo. So, the first cycling of Ca²⁺ within the heart could be driven by IP₃Rs, and this may underlie the initiation of cardiac pacemaking (Mery et al. 2005). Additional evidence for the importance of IP₃Rs in generating pacemaking action potentials is presented by Kapur & Banach (2007) in the current issue of The Journal of Physiology. These authors set out to understand the generation of spontaneous Ca²⁺ signals in stem cell-derived cardiomyocytes. Their in vitro differentiation conditions produce myocytes that strongly resemble cells from the developing sino-atrial node. This is the tissue within the right atrium that fires repetitive action potentials to initiate cardiac contraction. These cells display regular spontaneous global Ca²⁺ transients. By pharmacologically dissecting the channels involved in generating the Ca²⁺ transients, Kapur & Banach determined that IP₃Rs were responsible for the initiation of the signals. By itself, the IP₃-evoked Ca²⁺ release was modest, but it was amplified by surrounding RyRs via CICR. The amplified Ca²⁺ signal was able to depolarize the cells and trigger an even larger Ca²⁺ rise through the activation of sarcolemmal voltage-operate Ca²⁺ channels. The mechanism of pacemaking outlined by Kapur & Banach is essentially the same as that for IP₃R-triggered arrhythmias. The important difference being that one is a physiological process for co-ordinating the cardiac cycle, whilst the other is a potential means of disturbing heart rhythm.

Clearly, more work is required to establish why IP₃Rs are expressed within the heart. Current evidence suggests that they can have both beneficial and pathological consequences. The ability of IP₃Rs to open independently of other messengers makes them ideal candidates for acting as initiators of pacemaking in developing myocytes, or in the generation of spatially distinct Ca²⁺ signals to control gene transcription. However, the same independent activity can trigger harmful promiscuous Ca²⁺ transients.