Family affairs of intracellular Ca(2+)-release channels.

Abstract

Ca2+ release from intracellular Ca2+ stores plays important roles in the regulation of a vast array of cellular functions (Berridge et al. 2000). Two families of Ca2+-release channels, inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), each family consisting of three members, are expressed simultaneously in certain cells including neurons and smooth muscle cells. These Ca2+-release channels share structural similarities and are derived from a common ancestral Ca2+-release channel. Importantly, both types of Ca2+-release channels are sensitive to the cytosolic concentration of Ca2+ in a biphasic manner, and have a similar Ca2+ sensor region (Miyakawa et al. 2001). Recent results suggest that these Ca2+-release channels produce distinct Ca2+ signalling patterns in vascular smooth muscle cells that are thought to be antagonistic. Thus, IP3R generate Ca2+ waves and oscillations for contraction (Iino et al. 1994), whereas RyR generate Ca2+ sparks which, in turn, activate BK channels to cause hyperpolarisation and relaxation (Nelson et al. 1995). Since Ca2+ is the common activator of both RyR and IP3R, it seems possible that the two channels mutually activate each other. Boittin et al. (1999) reported that when rat portal vein smooth muscle cells were dialysed with antibody against RyR, the noradrenaline-induced response was diminished. Based on this finding, these authors proposed that RyR amplify the Ca2+ release via IP3R. On the other hand, the role of RyR in carbachol-induced Ca2+ response in intestinal smooth muscle cells was suggested to be minimal by an earlier work (Iino et al. 1993). Thus, collaboration of the two Ca2+-release channels requires further clarification. Now, Gordienko & Bolton (2002) in this issue of The Journal of Physiology present a new case indicating the collaboration of the two families, i.e. IP3R-mediated successive activation of Ca2+-release events via RyR. Gordienko & Bolton (2002) found two classes of spontaneous Ca2+-release events in rat portal vein smooth muscle cells, (unitary) Ca2+ sparks and large Ca2+ sparks. The authors propose that RyR produce Ca2+ sparks and that IP3R function as the fuse between adjacent sparks. Thus, the interaction results in the formation of large Ca2+ sparks. This conclusion was drawn from the results that pharmacological interventions of IP3-induced Ca2+ release inhibit the generation of large Ca2+ sparks while leaving unitary Ca2+ sparks unchanged. The data, based on multiple pharmacological interventions, collectively point to the role of IP3R in bunching of unitary Ca2+ sparks, although supporting data obtained by independent methods are awaited to back up the conclusion. Furthermore, the physiological roles of these spontaneous events require elucidation. The results of Gordienko & Bolton (2002) have generated new questions. The present hypothesis requires the continuous presence of a background level of IP3 concentration which is sufficient to induce Ca2+ release via IP3R upon an increase in Ca2+ concentration by a Ca2+ spark. If there is a sufficient level of resting IP3 concentration, a Ca2+ influx via voltage-dependent Ca2+ channels upon depolarisation may also induce Ca2+ release via the IP3R, because the IP3R are distributed throughout the cells. Does this really occur? The manner in which the large Ca2+ spark is confined to a small region near the nucleus (frequent discharge site) is another problem. If IP3R can be activated upon Ca2+ increase by the initial Ca2+ spark and are capable of activating adjacent RyR to generate secondary Ca2+ sparks, why is it that the local Ca2+ transients do not induce a global Ca2+ wave? This question may be answered if we assume localised condensation of the Ca2+ channel density near the large Ca2+ spark site. Is this really the case? Further studies are certainly required. The roles of Ca2+-release channels in the regulation of cellular functions are suggested in many cell types other than smooth muscle cells including central neurons. Although the crosstalk between RyR and IP3R may seem to be only a family problem among the Ca2+-release channels, its impact on cellular functions may be widespread. We have to keep our eyes on the family affairs.