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

Norepinephrine has for many years been known to have three major effects on the pancreatic β-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 Ca(2+) channels that increase intracellular Ca(2+) concentration ([Ca(2+)](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 [Ca(2+)](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 βγ 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 β-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by Gαi(1) and/or Gαi(2); and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that Gαo regulates the number of docked granules in the β-cell, and that Gαo(2) maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of Gαo(2), was initially called "islet activating protein." Finally, there is clear evidence that overexpression of α(2A)-adrenergic receptors in β-cells can cause type 2 diabetes.