title: Insulin receptor signaling for the proliferation of pancreatic β-cells: involvement of Ca2+ second messengers, IP3, NAADP and cADPR.
abstract: Insulin has an autocrine/paracrine role through insulin receptors in pancreatic β-cells. Herein, we show the insulin receptor signaling pathway underlying CD38/ADPR-cyclase activation for NAADP/cADPR formation to induce Ca2+ rise, ultimately resulting in β-cell proliferation. Binding of insulin on insulin receptors leads to the activation of IRS/Akt/PI3K/PLC. Activation of PLC generates IP3 and DAG; the former induces Ca (2+) release, resulting in activation of CD38/ADPR-cyclase for cADPR production via cGMP-dependent mechanism and the latter activates PKC, resulting in activation of ADPR-cyclase for NAADP synthesis. The NAADP-induced Ca (2+) signal is required for IP3-induced Ca (2+) release from the ER. CD38 plays an important role in insulin receptor signaling in β-cells by reflecting a declined sustained Ca (2+) signal, cADPR levels, and β-cell proliferation in response to insulin in CD38 (-/-) islets. However, evidence indicates that a hitherto-unidentified ADPR cyclase in addition to CD38 participates in insulin-induced signaling through cADPR and NAADP synthesis. In conclusion, insulin receptor signaling in β-cells employs three Ca (2+) signaling messengers, IP3, NAADP, and cADPR through a complex but concerted action of signaling molecules for Ca2+ signaling, which is involved in the proliferation of the islets.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Asif Iqbal
authors.initials: AI
authors.lastname: Shawl
authors.forename: Kwang-Hyun
authors.initials: KH
authors.lastname: Park
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000378:metabolism / Q000502:physiology*; D007295:Inositol Phosphates / Q000378:metabolism / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology; D011972:Receptor, Insulin / Q000378:metabolism* / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D007295:Inositol Phosphates; D008562:Membrane Glycoproteins; C118500:inositol 3,4,5-trisphosphate; D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D011972:Receptor, Insulin; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium