Small G proteins as key regulators of pancreatic digestive enzyme secretion

Abstract

Small GTP-binding (G) proteins act as molecular switches to regulate a number of cellular processes, including vesicular transport. Emerging evidence indicates that small G proteins regulate a number of steps in the secretion of pancreatic acinar cells. Diverse small G proteins have been localized at discrete compartments along the secretory pathway and particularly on the secretory granule. Rab3D, Rab27B, and Rap1 are present on the granule membrane and play a role in the steps leading up to exocytosis. Whether the function of these G proteins is simply to ensure appropriate targeting or if they are involved as regulatory molecules is discussed. Most evidence suggests that Rab3D and Rab27B play a role in tethering the secretory granule to its target membrane. Other Rabs have been identified on the secretory granule that are associated with different steps in the secretory pathway. The Rho family small G proteins RhoA and Rac1 also regulate secretion through remodeling of the actin cytoskeleton. Possible mechanisms for regulation of these G proteins and their effector molecules are considered.

Rab3D regulates amylase levels, not agonist-induced amylase release, in AR42J cells

“…Moreover, work from this laboratory and others have suggested that Rab3D may associate with subpopulations of mature ZG [19,20]. Despite the fact that numerous approaches have been employed to elucidate the function of Rab3D, the exact role of this GTPase in exocrine cells remains controversial (for review, see 21). Because of its localization on the ZG membrane, Rab3D was originally believed to be involved in late events in exocytosis.…”

Directing exocrine secretory vesicles to the apical membrane by actin cables generated by the formin mDia1

“…These secretory vesicles are separated from the apical plasma membrane by a dense actin network, termed the "terminal web" (5,6). In addition, several secretion-supporting roles have been assigned to subapical actin.…”

Molecular Machinery Regulating Exocytosis

“…The most highly conserved and best studied members of the Rho family, Rho1/A, Rac1 and Cdc42, play a crucial role in tethering and fusion of vesicles during regulated exocytosis (Ory & Gasman, 2011;Ridley, 2006;Williams, et al, 2009). Most Rho GTPases transiently localize at the plasma membrane, after being targeted to specific phosphoinositide-containing sub-domains.…”