Nucleotides and divalent cations as effectors and modulators of exocytosis in permeabilized rat mast cells

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Abstract
The idea that the universal trigger to exocytosis (the term inal step in the secretory process) is an elevation of the cytosol concentration of Ca2+, and that it is dependent on ATP, is no longer tenable. Working with streptolysin-O-permeabilized mast cells (and other myeloid cells) we have shown that non-hydrolysable analogues of GTP can stimulate exocytosis after depletion of Ca2+(i.e. at concentrations below 10-9m) and ATP. Such Ca2+- and ATP-independent exocytosis is strongly dependent on the presence of Mg2+, and the requirement for Mg2+declines as the concentration of Ca2+is brought up to 10-7m . We argue that Ca2+serves to regulate the binding of guanine nucleotides to G e, a GTP-binding protein that regulates exocytosis through its interaction with CE, a calcium-binding protein which serves as an intracellular pseudo-receptor. The onset of exocytosis, following provision of Ca2+and guanine nucleotides to the permeabilized cells, is preceded by delays which are sensitive to the order of provision of the two effectors (i.e. Ca2+and guanine nucleotides), the presence or absence of Mg2+, and the identity of the activating guanine nucleotide. In view of the similarity of these features with the activation kinetics of adenylyl cyclase, we argue that GEbehaves as a member of the heterotrimeric class of signal transducing G-proteins such as Gs.

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