Abstract
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 Ca(2+) -regulated exocytosis, where it functions in an inhibitory capacity controlling recruitment of secretory vesicles into a releasable pool at the plasma membrane. The effector by which Rab3A exerts its inhibitory effect is unclear as the Rab3A effectors 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 overexpression of Noc2 in PC12 cells has a direct inhibitory effect upon Ca(2+)-triggered exocytosis in permeabilized cells. We demonstrate specific nucleotide-dependent binding of Noc2 to Rab3A and show that the inhibition of exocytosis is dependent upon this interaction since Rab3A binding-deficient mutants of Noc2 do not inhibit exocytosis. We propose that Noc2 may be a negative effector for Rab3A in regulated exocytosis of dense-core granules from endocrine cells.
Highlights
The secretory pathway of eukaryotic cells is essential to the maintenance of cellular architecture and, in certain specialized cell types, serves as the basis for cell-cell communication
Rab3A is a neural/ neuroendocrine-specific member of the Rab family involved in Ca2؉ -regulated exocytosis, where it functions in an inhibitory capacity controlling recruitment of secretory vesicles into a releasable pool at the plasma membrane
Noc2 appears to be predominantly expressed in endocrine and neuroendocrine tissues, and, it is expressed at low levels in brain, it may represent a dense core granule-specific Rab3A effector
Summary
The secretory pathway of eukaryotic cells is essential to the maintenance of cellular architecture and, in certain specialized cell types, serves as the basis for cell-cell communication. Rab3A is a mammalian, neural/endocrine-specific Rab protein present on synaptic vesicle and secretory granules [7,8,9,10] that appears to be involved in the control of Ca2ϩ-regulated fusion of vesicles with the plasma membrane. The use of mutagenesis and analysis of gene knockouts has ruled out a requirement for Rab3A interaction for these effects and have eliminated Rabphilin 3A or RIM as the inhibitory effectors of Rab3A [31,32,33,34] Another candidate Rab3Ainteracting protein [35] that has been suggested to be involved in the inhibition of exocytosis [32] is calmodulin. This paper is available on line at http://www.jbc.org tion from transfected PC12 cells, indicating a role for Noc in some aspect of regulated secretion from endocrine cell types, an indirect action on Ca2ϩ channels or the Ca2ϩ signal could not be ruled out
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