Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion.

Secretion of the peptide hormone insulin from pancreatic beta cells constitutes an important step in the regulation of body homeostasis. Insulin is stored in large dense core vesicles and released by exocytosis, a multistage process involving transport of vesicles to the plasma membrane, their docking, priming and finally their fusion with the plasma membrane. Some of the protein components necessary for this process have been identified in beta cells. The export of potent and potentially harmful substances has to be tightly controlled. The secretory response in pancreatic beta cells requires the concerted action of nutrients together with enteric hormones and neurotransmitters acting on G-protein coupled receptors. It is well established that glucose and other metabolizable nutrients depolarize the beta-cell membrane and the ensuing Ca2+ influx through voltage-dependent channels constitutes a main stimulus for insulin exocytosis. Theoretical considerations and recent observations suggest in addition an organizing role for the Ca2+ channel similar to neurotransmission. A second regulatory control on exocytosis is exerted by monomeric and heterotrimeric G-proteins. The monomeric GTPase Rab3A controls insulin secretion through cycling between a guanosine triphosphate liganded vesicle-bound form and a guanosine diphosphate liganded, cytosolic form. The effect of neurohormones is transduced by the heterotrimeric GTPases. Whereas pertussis-toxin sensitive alpha-subunits exert direct inhibition at the level of exocytosis, the Gbeta gamma-subunits are required for stimulation. It is possible that these GTPases exert immediate regulation, while protein kinases and phosphatases may modulate long-term adaptation at the exocytotic machinery itself. The molecular nature of their activators and effectors still await identification. Insights into the progression of the exocytotic vesicle from docking to fusion and how these processes are precisely regulated by proteins and second messengers may provide the basis for new therapeutic principles.