Rab-αGDI activity is regulated by a Hsp90 chaperone complex

The Rab-specific αGDP-dissociation inhibitor (αGDI) regulates the recycling of Rab GTPases. We have now identified a novel αGDI complex from synaptic membranes that contains three chaperone components: Hsp90, Hsc70 and cysteine string protein (CSP). We find that the αGDI–chaperone complex is dissociated in response to Ca(2+)-induced neurotransmitter release, that chaperone complex dissociation is sensitive to the Hsp90 inhibitor geldanamycin (GA) and that GA inhibits the ability of αGDI to recycle Rab3A during neurotransmitter release. We propose that αGDI interacts with a specialized membrane-associated Rab recycling Hsp90 chaperone system on the vesicle membrane to coordinate the Ca(2+)-dependent events triggering Rab-GTP hydrolysis with retrieval of Rab-GDP to the cytosol.