title: Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression.
abstract: Mouse pancreatic β- and α-cells are equipped with voltage-gated Na(+) currents that inactivate over widely different membrane potentials (half-maximal inactivation (V0.5) at -100 mV and -50 mV in β- and α-cells, respectively). Single-cell PCR analyses show that both α- and β-cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α subunits, but their relative proportions differ: β-cells principally express Nav1.7 and α-cells Nav1.3. In α-cells, genetically ablating Scn3a reduces the Na(+) current by 80%. In β-cells, knockout of Scn9a lowers the Na(+) current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a(-/-) islets but unaffected in Scn9a-deficient islets. Thus, Nav1.3 is the functionally important Na(+) channel α subunit in both α- and β-cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30 mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Chibalina
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Bengtsson
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Lukas N
authors.initials: LN
authors.lastname: Groschner
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Reshma
authors.initials: R
authors.lastname: Ramracheya
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK.
authors.forename: Nils J G
authors.initials: NJ
authors.lastname: Rorsman
authors.affiliation: Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802, München, Germany Institut für Pharmakologie und Toxikologie, Eberhard-Karls Universität, Wilhelmstr. 56, 72074, Tübingen, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Leiss
authors.affiliation: Molecular Nociception Group, University College London (UCL), Gower Street, London, WC1E 6BT, UK Biomedical Science, University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nassar
authors.affiliation: Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802, München, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Welling
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802, München, Germany FOR 923, Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Str. 29, 80802, München, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Molecular Nociception Group, University College London (UCL), Gower Street, London, WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK Department of Neuroscience and Physiology, Sahlgren's Academy, University of Göteborg, Box 430, SE40530, Göteborg, Sweden patrik.rorsman@ocdem.ox.ac.uk.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D020033:Protein Isoforms; D021122:Protein Subunits; D012964:Sodium / Q000502:physiology*
chemical_list: D007328:Insulin; D062552:NAV1.3 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009498:Neurotoxins; D020033:Protein Isoforms; D021122:Protein Subunits; D012964:Sodium; D005947:Glucose