Larry H Bernstein
This is a review of the role of calmodulin and protein kinase C inregulation of Ca++ - stimulated secretion. The molecular mechanisms underlying the Ca2+ regulation of hormone and neurotransmitter release are largely unknown. Using a reconstituted [3H] norepinephrine release assay in permeabilized PC12 cells, we found essential proteins that support the triggering stage of Ca2+-stimulated exocytosis are enriched in an EGTA extract of brain membranes. Fractionation of this extract allowed purification of two factors that stimulate secretion in the absence of any other cytosolic proteins. These are calmodulin and protein kinase Ca (PKCa). Their effects on secretion were confirmed using commercial and recombinant proteins. Calmodulin enhances secretion in the absence of ATP, whereas PKC requires ATP to increase secretion, suggesting that phosphorylation is involved in PKC-mediated stimulation but not calmodulin mediated stimulation. Both proteins modulate the half-maximal increase was elicited by 3 nM PKC and 75 nM calmodulin. These results suggest that calmodulin and PKC increase Ca2+-activated exocytosis by directly modulating the membrane- or cytoskeleton-attached exocytic machinery downstream of Ca2+ elevation.
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