Rab3s

Rab3s are a group of small GTPases in the Rab family that regulate regulated exocytosis. In mammals, the Rab3 subfamily includes Rab3A, Rab3B, Rab3C, and Rab3D. They are highly expressed in neurons and secretory cells, where they associate with secretory vesicles and dense-core granules to participate in controlled exocytosis.

Biochemically, Rab3 proteins are about 23–25 kDa and cycle between GDP- and GTP-bound states. Their activity is controlled by guanine nucleotide exchange factors (GEFs) that promote the active GTP-bound form and GTPase-activating proteins (GAPs) that accelerate hydrolysis to GDP. Rab3 proteins are prenylated at their C-termini, which anchors them to membranes; cytosolic Rab3 is typically bound to Rab GDI, which shuttles the protein to membranes as needed.

Functionally, the GTP-bound Rab3 on secretory vesicles interacts with effector proteins such as Rabphilin-3A and Rim family members, as well as other components of the exocytic machinery, to influence vesicle docking, priming, and Ca2+-triggered fusion. Hydrolysis of GTP to GDP leads to dissociation from effectors and recycling of Rab3 back to the cytosol by GDI. The precise contributions of each isoform vary by tissue, but Rab3A is the best characterized in neurons, where it modulates release probability and short-term synaptic plasticity. In pancreatic beta cells and other secretory cell types, Rab3 proteins participate in regulated secretion of hormones and enzymes.

Rab3 proteins are conserved across vertebrates and serve as models for understanding the control of exocytosis and vesicle priming. Ongoing research aims to clarify isoform-specific roles and interactions with effector and regulatory proteins.