Phospholipase C signaling and calcium influx

Abstract

Calcium signaling is a process whereby the extremely low cytoplasmic Ca2+ concentration increases in a deliberate and specific manner to trigger downstream cellular events. Virtually every tissue, and even every cell type in the human body utilizes some form of Ca2+ signaling to function or survive. There are many mechanisms which can generate Ca2+ signals; perhaps the most widely encountered, and the focus of this review, is a mechanism involving a lipid metabolizing enzyme, phospholipase C. Phospholipase C is a truly remarkable signalling moiety. We know of no other single enzyme that can produce (or modulate), directly, three distinct signals: inositol 1,4,5-trisphosphate (IP3), diacylglycerol, and phosphatidylinositol 4,5-bisphosphate (PIP2). The association of phospholipase C with Ca2+ signaling dates back arguably to experiments published by Lowell Hokin (Hokin, 1966) establishing the relative independence of inositol lipid turnover from Ca2+ signaling. It was just this independence from Ca2+ signaling that suggested to Bob Michell that inositol lipid turnover, initiated by phospholipase C-mediated inositide breakdown, was upstream of Ca2+ signaling (Michell, 1975;Michell et al., 1977). It was later established that the initiating reaction was the breakdown of the relatively minor inositol lipid, PIP2(Creba et al., 1983;Weiss et al., 1982;Berridge, 1983), leading Mike Berridge (Berridge, 1983)to propose that the released head group, IP3, could function as a Ca2+ signaling second messenger. This was rapidly confirmed experimentally by Berridge and his collaborators (Streb et al., 1983), and subsequently by other investigators (Burgess et al., 1984;Prentki et al., 1984;Joseph et al., 1984;Hirata et al., 1984;Biden et al., 1984;Whittaker & Irvine, 1984;Suematsu et al., 1984;Brown & Rubin, 1984). All three of the three phospholipase C derived signals regulate ion channels. Numerous ion channels require PIP2 for optimal activity and thus can be negatively regulated by phospholipase C activity (Suh & Hille, 2005;Hilgemann et al., 2001). The IP3 receptor in an intracellular calcium permeable channel activated by the phospholipase C product, IP3 (Mikoshiba, 2007). However, this review will focus primarily on plasma membrane channels that are activated as a consequence of phospholipase C activation. There are two major categories of such channels, the store-operated channels, and the TRPC channels.1