Calcium calmodulin and hormone secretion.

As long ago as 1970, it was proposed that Ca2+ can act as a 'second messenger' like cAMP (Rasmussen & Nagata, 1979). The recognition that calmodulin is a major Ca2+ binding protein in non-muscle cells has prompted the suggestion that calmodulin may serve an analogous role for Ca2+ to that served by protein kinase for cAMP (Wang & Waisman, 1979), or at least to the regulatory subunit of the cyclic nucleotide-dependent kinases. It is becoming clear that calmodulin probably does play a role in stimulus secretion coupling in endocrine cells. Nevertheless, some of the experimental approaches which have led to this rather tentative conclusion do induce some doubts, as we have attempted to indicate. Many of the pharmacological agents used in the studies cited in this review are not specific in their interaction with calmodulin. For example, the phenothiazines also inhibit phospholipid-sensitive protein kinase. The introduction of more specific drugs, such as the naphthalene sulphonamides, may lead to a clearer picture of the role of calmodulin in hormone secretion. Relationships probably exist between cyclic nucleotides, calcium, calmodulin, phosphatidylinositol (PI) turnover and phospholipids in the overall control of the secretory process (see Fig. 1). There is considerable evidence that calcium is the primary internal signal initiating exocytosis of hormone from many glands. However, it appears that cyclic nucleotides can modulate the calcium signal either positively or negatively and it is possible that cAMP and calcium can separately activate secretion. The presence of both calmodulin-activated adenylate cyclase and cyclic nucleotide phosphodiesterase in the same tissue would appear to suggest either spatial or temporal control mechanisms or that (diagram; see text) the calcium requirement for calmodulin activation differs between the two enzymes. The true explanation is probably far more complex and involves perhaps as yet unknown factors that can differentially influence the activity of calmodulin itself in membranes and in cytosol. Berridge (1982) and Rasmussen (1980) give detailed accounts and review current hypotheses regarding relationships between the cyclic nucleotide and calcium second messenger systems. The various possible interrelationships of the putative messengers have been encompassed by the term 'Synarchic regulation' (Rasmussen, 1980). These concepts and the elucidation of the mechanisms by which cyclic AMP and calcium are involved in the control of secretion from particular cell types will make fascinating reading over the next few years.(ABSTRACT TRUNCATED AT 400 WORDS)