title: Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.
abstract: Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.
authors.affiliation: Molecular Physiology & Biophysics, Vanderbilt University Medical Centre, Nashville, TN 37232, USA. richard.benninger@vanderbilt.edu
authors.forename: R K P
authors.initials: RK
authors.lastname: Benninger
authors.forename: W Steven
authors.initials: WS
authors.lastname: Head
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Leslie S
authors.initials: LS
authors.lastname: Satin
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D017630:Connexins / Q000172:deficiency / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D017629:Gap Junctions / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D000097004:Gap Junction delta-2 Protein
chemical_list: D002118:Calcium; D017630:Connexins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D007328:Insulin; D000097004:Gap Junction delta-2 Protein