A direct inhibitory role for the Rab3-specific effector, Noc2, in Ca2+-regulated exocytosis in neuroendocrine cells

Rab proteins comprise a family of GTPases, conserved from yeast to mammals, which are integral components of membrane trafficking pathways. Rab3A is a neural/neuroendocrine-specific member of the Rab family involved in Ca2+-r egulated exocytosis, where it functions in an inhibitory capacity controlli ng recruitment of secretory vesicles into a releasable pool at the plasma m embrane. The effector by which Rab3A exerts its inhibitory effect is unclea r as the Rab3A effecters Rabphilin and RIM have been excluded from for this role. One putative Rab3A effector in dense-core granule exocytosis is the cytosolic zinc finger protein, Noc2, We have established that overexpressio n of Noc2 in PC12 cells has a direct inhibitory effect upon Ca2+-triggered exocytosis in permeabilized cells. We demonstrate specific nucleotide-depen dent binding of Noc2 to Rab3A and show that the inhibition of exocytosis is dependent upon this interaction since Rab3A binding-deficient mutants of N oc2 do not inhibit exocytosis, We propose that Noc2 may be a negative effec tor for Rab3A in regulated exocytosis of dense-core granules from endocrine eels.