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Na+ current properties in islet alpha- and beta-cells reflect cell-specific Scn3a and Scn9a expression

Journal article
Authors Q. Zhang
M. V. Chibalina
M. Bengtsson
L. N. Groschner
R. Ramracheya
N. J. G. Rorsman
V. Leiss
M. A. Nassar
A. Welling
F. M. Gribble
F. Reimann
F. Hofmann
J. N. Wood
Frances M. Ashcroft
Patrik Rorsman
Published in Journal of Physiology-London
Volume 592
Issue 21
Pages 4677-4696
ISSN 0022-3751
Publication year 2014
Published at Institute of Neuroscience and Physiology
Pages 4677-4696
Language en
Links dx.doi.org/10.1113/jphysiol.2014.27...
Keywords GATED SODIUM-CHANNELS, K-ATP CHANNELS, MOUSE PANCREATIC-ISLETS, B-CELLS, GLUCAGON-SECRETION, INSULIN-SECRETION, DELTA-CELLS, GLUCOSE-HOMEOSTASIS, DIABETES-MELLITUS, INTACT ISLETS, Neurosciences, Physiology, SLER S, 1992, DIABETES, V41, P1221, ESSEL DM, 1990, JOURNAL OF MEMBRANE BIOLOGY, V116, P273
Subject categories Neurosciences

Abstract

- and -cells express both Na(v)1.3 and Na(v)1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in - and -cells. Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells. Islet Na(v)1.7 channels are locked in an inactive state due to an islet cell-specific factor. Mouse pancreatic - and -cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation (V-0.5) at -100mV and -50mV in - and -cells, respectively). Single-cell PCR analyses show that both - and -cells have Na(v)1.3 (Scn3) and Na(v)1.7 (Scn9a) subunits, but their relative proportions differ: -cells principally express Na(v)1.7 and -cells Na(v)1.3. In -cells, genetically ablating Scn3a reduces the Na+ current by 80%. In -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, Na(v)1.3 is the functionally important Na+ channel subunit in both - and -cells because Na(v)1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Na(v)1.7 sequence in brain and islets is identical and yet the V-0.5 for inactivation is >30mV more negative in -cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.

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