Intimate Plasma Membrane–ER Interactions Underlie Capacitative Calcium Entry: “Kissin' Cousins”

The studies of Patterson et al. 1999xPatterson, R.L., van Rossum, D.B., and Gill, D.L. Cell. 1999; 98: 487–499Abstract | Full Text | Full Text PDF | PubMed | Scopus (355)See all ReferencesPatterson et al. 1999 and Yao et al. 1999xYao, Y., Ferrer-Montiel, A.V., Montal, M., and Tsien, R.Y. Cell. 1999; 98: 475–485Abstract | Full Text | Full Text PDF | PubMed | Scopus (216)See all ReferencesYao et al. 1999 argue against a simple, diffusible signal from the ER to the PM and suggest rather a mechanism of direct interaction between the PM and ER or other underlying cellular structure. When the data of Kiselyov et al. 1999xKiselyov, K., Mignery, G.A., Zhu, M.X., and Muallem, S. Mol. Cell. 1999; 4: 423–429Abstract | Full Text | Full Text PDF | PubMed | Scopus (214)See all ReferencesKiselyov et al. 1999 are considered, a simple conclusion is that this interaction involves the IP3 receptor of the ER and a PM calcium channel, perhaps a member of the TRP channel family. On the other hand, the data of Yao et al. may suggest a potentially more complex mechanism involving the insertion into the PM of calcium channels, or of components necessary for their activation. However, as shown by a number of studies, including those of Yao et al. and Patterson et al., cytoskeletal disruption generally has little or no effect on capacitative calcium entry, while most secretory systems are affected by this maneuver in either a positive or negative manner. Also, Yao et al. failed to detect an effect of BoNT B or C, yet another study has shown that these toxins are effective in blocking secretion in Xenopus oocytes (Quick et al. 1997xQuick, M.W., Corey, J.L., Davidson, N., and Lester, H.A. J. Neurosci. 1997; 17: 2967–2979PubMedSee all ReferencesQuick et al. 1997). Finally, most secretory systems require calcium and are generally activated by rises in cytoplasmic calcium, while capacitative calcium entry is strongly inhibited by cytoplasmic calcium. An alternative interpretation of the data of Yao et al. is that proteins involved in secretion in other pathways (or homologs of these proteins) function to facilitate spatial orientation and docking of PM proteins and ER proteins in response to depletion of Ca2+ from the critical pools, and this docking occurs in the absence of membrane fusion. Two working models are depicted in Figure 1Figure 1. PM channels may be loosely if at all associated with underlying IP3 receptors, depletion of stores then causes these proteins to become more tightly coupled, and the TRP channels become activated. To encompass the evidence suggesting an exocytotic mechanism, the IP3 receptor in the ER membrane and TRP in a semidocked vesicle may be associated, and activation, by Ca2+ depletion, leads to the reversible fusion of the vesicle such that extracellular Ca2+ has access to the open channel. These proposals are nothing more than attempts to visualize or formalize models that are compatible with the existing data, and certainly they do not encompass all possibilities. For example, as discussed by Patterson et al., one can envision something in between the two in which vesicles or endoplasmic reticulum and PM interact in a rapid, nonfusing manner, such as the so-called “kiss-and-run” mode of secretion (Neher 1993xNeher, E. Nature. 1993; 363: 497–498CrossRef | PubMed | Scopus (26)See all ReferencesNeher 1993).Figure 1Models for Coupling Depletion of Intracellular Calcium Stores to Activation of PM Capacitative Calcium Entry Channels(Top) A conformational coupling model is depicted similar to the one proposed by Berridge 1995xBerridge, M.J. Biochem. J. 1995; 312: 1–11CrossRef | PubMedSee all ReferencesBerridge 1995 following on the original proposal by Irvine 1990xIrvine, R.F. FEBS Lett. 1990; 263: 5–9CrossRef | PubMed | Scopus (466)See all ReferencesIrvine 1990. Receptor (R) activation of phospholipase C (PLC) through an appropriate G protein (G) generates IP3 depleting intracellular Ca2+ stores in the ER. This depletion causes IP3 receptors (IP3R) to associate with TRP channels in the PM activating the channels. Recent findings suggest that the IP3 receptors involved in this signaling must be liganded with IP3 for this coupling or channel activation to occur (7xKiselyov, K., Xu, X., Mozhayeva, G., Kuo, T., Pessah, I., Mignery, G., Zhu, X., Birnbaumer, L., and Muallem, S. Nature. 1998; 396: 478–482CrossRef | PubMed | Scopus (497)See all References, 8xKiselyov, K., Mignery, G.A., Zhu, M.X., and Muallem, S. Mol. Cell. 1999; 4: 423–429Abstract | Full Text | Full Text PDF | PubMed | Scopus (214)See all References). Because this pathway can be activated in the absence of PLC activation, sufficient IP3 may be provided under basal conditions by closely associated PLC. This close association between PLC and TRP perhaps may involve an as yet uncharacterized protein (?) analogous to INAD in the Drosophila photoreceptor. Note that the IP3 receptors involved in regulating the TRP channels are likely distinct from the population of IP3 receptors chiefly involved in release of intracellular Ca2+ when IP3 is increased by receptor activation.(Bottom) In an exocytosis model, TRP channels exist in secretory vesicles and when stores are depleted by IP3, these vesicles fuse with the PM allowing inflow of Ca2+ through the activated channels. From the data of Yao et al. (Yao et al. 1999xYao, Y., Ferrer-Montiel, A.V., Montal, M., and Tsien, R.Y. Cell. 1999; 98: 475–485Abstract | Full Text | Full Text PDF | PubMed | Scopus (216)See all ReferencesYao et al. 1999), secretory SNARE proteins such SNAP-25 may be involved; the identities of other SNARE proteins in this mechanism are currently uncertain, and in the model are designated simply as an additional t-SNARE and v-SNARE (see text). To accommodate the data from other recent work, the TRP proteins in the secretory vesicles are depicted as interacting with ER IP3 receptors that convey information about Ca2+ depletion and initiate events leading to fusion.View Large Image | View Hi-Res Image | Download PowerPoint SlideThere are obviously still a number of issues to be resolved with these new findings and these suggested mechanisms; how are these signaling complexes assembled, and what are the key protein partners that make this pathway work under physiological conditions? What is the nature of the endogenous calcium channel—a heteromultimer of TRP proteins, or a complex of completely different proteins not yet considered? And despite the strong evidence for a conformational coupling mechanism in these particular systems, the possibility that PM channels could be regulated by diffusible messengers in other cellular systems or in other signaling pathways cannot be ruled out. We may be entering a new era of research on capacitative calcium entry when we will learn the important molecular details of this fascinating and mysterious phenomenon.