title: Insulin secretion and Ca2+ dynamics in β-cells are regulated by PERK (EIF2AK3) in concert with calcineurin.
abstract: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) (EIF2AK3) is essential for normal development and function of the insulin-secreting β-cell. Although genetic ablation of PERK in β-cells results in permanent neonatal diabetes in humans and mice, the underlying mechanisms remain unclear. Here, we used a newly developed and highly specific inhibitor of PERK to determine the immediate effects of acute ablation of PERK activity. We found that inhibition of PERK in human and rodent β-cells causes a rapid inhibition of secretagogue-stimulated subcellular Ca(2+) signaling and insulin secretion. These dysfunctions stem from alterations in store-operated Ca(2+) entry and sarcoplasmic endoplasmic reticulum Ca(2+)-ATPase activity. We also found that PERK regulates calcineurin, and pharmacological inhibition of calcineurin results in similar defects on stimulus-secretion coupling. Our findings suggest that interplay between calcineurin and PERK regulates β-cell Ca(2+) signaling and insulin secretion, and that loss of this interaction may have profound implications in insulin secretion defects associated with diabetes.
authors.affiliation: Department of Biology, Center of Cellular Dynamics, Pennsylvania State University, Pennsylvania 16802.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Biology, Center of Cellular Dynamics, Pennsylvania State University, Pennsylvania 16802.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: McGrath
authors.affiliation: Department of Medicine, Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, New York 13210.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kopp
authors.affiliation: Department of Medicine, Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, New York 13210.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.affiliation: Department of Biology, Center of Cellular Dynamics, Pennsylvania State University, Pennsylvania 16802.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Biology, Center of Cellular Dynamics, Pennsylvania State University, Pennsylvania 16802.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Biology, Center of Cellular Dynamics, Pennsylvania State University, Pennsylvania 16802. Electronic address: drc9@psu.edu.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cavener
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D019703:Calcineurin; D002118:Calcium; D007328:Insulin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019892:eIF-2 Kinase; C460640:EIF2AK3 protein, human
keywords: Calcineurin; Calcium Dynamics; Calcium Imaging; Diabetes; ER Stress; Insulin Secretion; PERK; Sarcoplasmic Endoplasmic Reticulum-Calcium ATPase; Store-operated Calcium Entry