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1 Laboratory of Molecular Signalling, Babraham Institute, Cambridge CB2 4AT, UK
2 Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1 PD, UK Email:
martin.bootman{at}bbsrc.ac.uk
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.
References
Bootman MD, Berridge MJ & Roderick HL (2002). Curr Biol 12, R563–R565.[CrossRef][Medline]
Kapur N & Banach K (2007). J Physiol 581, 1113–1127.
Li X, Zima AV, Sheikh F, Blatter LA & Chen J (2005). Circ Res 96, 1274–1281.
Mery A, Aimond F, Menard C, Mikoshiba K, Michalak M & Puceat M (2005). Mol Biol Cell 16, 2414–2423.
Perez PJ, Ramos-Franco J, Fill M & Mignery GA (1997). J Biol Chem 272, 23961–23969.
Proven A, Roderick HL, Conway SJ, Berridge MJ, Horton JK, Capper SJ & Bootman MD (2006). J Cell Sci 119, 3363–3375.
Woodcock EA & Matkovich SJ (2005). Pharmacol Ther 107, 240–251.[CrossRef][Medline]
Wu X, Zhang T, Bossuyt J, Li X, McKinsey TA, Dedman JR, Olson EN, Chen J, Brown JH & Bers DM (2006). J Clin Invest 116, 675–682.[CrossRef][Medline]
Related Article
J. Physiol. 2007 581: 1113-1127.
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