Molecular Biological Studies of Calcium Signaling in Insulin Secretion ; their implication for the development of diabetes mellitus

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Intracellular calcium[Ca^<2+>]i is the principal signal for insulin secretion. Since major pathways causing an increase in [Ca^<2+>]i in pancreatic beta-cells are the influx across beta-cell membrane and the mobilization from intracellular calcium stores, the proteins involved in these pathways play crucial roles in the regulation insulin secretion. We have cloned and characterized a aopha1-subunit of rat beta-cell/neuroendocrine type voltage-dependent calcium (VDCC).Functional expression using CHO CELLS AND Xenopus oocytes shows that coexpression of the aopha1 and beta subunit generates a typical L-type VDCC activity, suggesting that the beta-cell/neuroendocrine type VDCC plays a role in insulin secretion. We have determined the structure of the human gene for the alpha1 subunit of beta-cell/neuroendocrine type VDCC.The gene has been localized to chromosome 3, band p14.3. The gene spans more than 120kb and has 50 exons. Analysis of sequence variations of this gene in non-insulin depen … More dent diabetes mellitus (NIDDM) is currently underway. We have also cloned a cDNA encoding a third subtype of inositol 1,4,5 triphosphate (IP3) receptor (IP3R-3) expressed in pancreatic islets and a clonal beta-cell line. Since some insulin secretagogues such as CCK and acetylcholine stimulate insulin secretion via PI hydrolysis, the IP3R-3 is suggested to be involved in the regulation of insulin. Many hormones and neurotransmtters are known to modulate insulin secretion through their specific receptors.We have cloned cDNAs encoding a somatostatin receptor (SSTR-3) and a pituitary adenylyl cyclase-activating, polypeptide (PACAP) receptor (PACAPR-3) expressed in pancreatic islets. Functional expression of PACAPR-3 shows that it can be coupled to phospholipase C as well as to adenylyl cyclase, suggesting that PACAPR-3 is involved in calcium signaling in insulin secretion. In conclusion, our studies have clarified molecular basis for some of the important factors involved in calcium signaling in insulin secretion and have provided valuable insight into the contribution of these genes to the development of NIDDM as well as the understanding of the molecular mechanisms of insulin secretion. Less