Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins

Straub SG, Sharp GW. Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins. Am J Physiol Cell Physiol 302: C1687-C1698, 2012. First published April 4, 2012; doi:10.1152/ajpcell.00282.2011.-Norepinephrine has for many years been known to have three major effects on the pancreatic beta-cell which lead to the inhibition of insulin release. These are activation of K+ channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca2+ channels that increase intracellular Ca2+ concentration ([Ca2+](i)) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a distal effect that occurs downstream of increased [Ca2+](i) to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein beta gamma subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the beta-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by G alpha i(1) and/or G alpha i(2); and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that G alpha o regulates the number of docked granules in the beta-cell, and that G alpha o(2) maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of G alpha o(2), was initially called islet activating protein. Finally, there is clear evidence that overexpression of alpha(2A)-adrenergic receptors in beta-cells can cause type 2 diabetes.