On the calcium receptor activating exocytosis: inhibitory effects of calmodulin-interacting drugs on rat mast cells.

1. A series of neuroleptic drugs (five phenothiazines, imipramine, and pimozide) and the smooth muscle relaxant W-7, which all inhibit calcium-calmodulin-activated processes inhibited rat mast cell secretion elicited by antigen, by 48/80, and by the calcium ionophore A23187. 2. Neither the phenothiazines nor W-7 reduced 45Ca uptake in response to A23187. The drugs thus exert an inhibitory action distal to the rise in intracellular Ca ions that activates exocytosis. 3. Chlorpromazine sulphoxide, which shares several membrane-perturbing actions of the phenothiazines but is a weak inhibitor of calmodulin, did not inhibit secretion. Moreover, the inhibitory effects of the phenothiazines were not overcome by a 5- or 10-fold increase in the concentration of calcium, which should counter unspecific membrane effects. 4. The inhibitory effects of the various neuroleptic drugs appeared to be related to their ability to inhibit calmodulin because the individual potencies of these compounds on secretion evoked by 48/80 or A23187 correlated significantly with their reported potencies in inhibiting calmodulin-activated processes. (The greater potency and different rank order of these compounds on secretion evoked by antigen suggests an additional inhibitory action, perhaps involving Ca entry.) 5. These results, which parallel those obtained with drugs of this sort in smooth muscle where calmodulin seemingly functions as the Ca receptor activating contraction, strengthen the view that calmodulin, or some calmodulin-like protein, is the Ca receptor activating exocytosis.