Zhang_2016_Am.J.Physiol.Endocrinol.Metab_310_e874

Contact between beta-cells is necessary for their normal function. Identification of the proteins mediating the effects of beta-cell-to-beta-cell contact is a necessary step towards gaining a full understanding of the determinants of beta-cell function and insulin secretion. The secretory machinery of the beta-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the trans-cellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such trans-cellular interactions, important for both synaptic and beta-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here we test the role of another synaptic-cleft protein, CADM1, in insulinoma cells and in rat and human islet beta-cells. We find that CADM1 is a predominant CADM isoform in beta-cells. In INS-1 cells and primary beta-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we find that CADM1 also influences insulin secretion in a trans-cellular manner. We ask whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on beta-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing beta-cell dysfunction in diabetes.