CaV2.3 calcium channels control second-phase insulin release
Xingjun Jing, … , Patrik Rorsman, Erik Renström
Xingjun Jing, … , Patrik Rorsman, Erik Renström
Published January 3, 2005
Citation Information: J Clin Invest. 2005;115(1):146-154. https://doi.org/10.1172/JCI22518.
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Article Metabolism

CaV2.3 calcium channels control second-phase insulin release

Abstract

Concerted activation of different voltage-gated Ca2+ channel isoforms may determine the kinetics of insulin release from pancreatic islets. Here we have elucidated the role of R-type CaV2.3 channels in that process. A 20% reduction in glucose-evoked insulin secretion was observed in CaV2.3-knockout (CaV2.3–/–) islets, close to the 17% inhibition by the R-type blocker SNX482 but much less than the 77% inhibition produced by the L-type Ca2+ channel antagonist isradipine. Dynamic insulin-release measurements revealed that genetic or pharmacological CaV2.3 ablation strongly suppressed second-phase secretion, whereas first-phase secretion was unaffected, a result also observed in vivo. Suppression of the second phase coincided with an 18% reduction in oscillatory Ca2+ signaling and a 25% reduction in granule recruitment after completion of the initial exocytotic burst in single CaV2.3–/– β cells. CaV2.3 ablation also impaired glucose-mediated suppression of glucagon secretion in isolated islets (27% versus 58% in WT), an effect associated with coexpression of insulin and glucagon in a fraction of the islet cells in the CaV2.3–/– mouse. We propose a specific role for CaV2.3 Ca2+ channels in second-phase insulin release, that of mediating the Ca2+ entry needed for replenishment of the releasable pool of granules as well as islet cell differentiation.

Authors

Xingjun Jing, Dai-Qing Li, Charlotta S. Olofsson, Albert Salehi, Vikas V. Surve, José Caballero, Rosita Ivarsson, Ingmar Lundquist, Alexey Pereverzev, Toni Schneider, Patrik Rorsman, Erik Renström

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Figure 1

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Whole-cell Ca2+ currents in islet cells from WT and CaV2.3–/– mice. (A) ...
Whole-cell Ca2+ currents in islet cells from WT and CaV2.3–/– mice. (A) Whole-cell Ca2+ currents (i) evoked by a 300-ms voltage-clamp depolarization (V) in WT CaV2.3+/+ (black) and CaV2.3–/– (gray) β cells. β cells were identified by exhibiting half-maximal Na+ channel inactivation at membrane potentials (V) lower than –100 mV (half-maximal inactivation at –102 mV; inset). (B) Average integrated current-voltage (Q-V) relationships. Data are mean values ± SEM in 10 WT (filled circles) and 10 CaV2.3–/– (shaded circles) β cells. *P < 0.05. (C) Whole-cell Ca2+ currents were recorded as in A, but using CaV2.3–/– β cells. The recordings were made under control conditions (lower gray line) in the presence of R-type Ca2+ channel blocker SNX482 (100 nM; black line) and after addition of L-type Ca2+ channel inhibitor isradipine (isr) (2 μM; upper gray line). (D) Average Q-V relationships representing mean values ± SEM in 4 CaV2.3–/– β cells under control conditions (shaded circles), in the presence of SNX482 (filled circles), and after addition of isradipine (open circles). *P < 0.05, **P < 0.01, control versus SNX482 plus isradipine. (E) Whole-cell Ca2+ currents were recorded as in A, but in α cells identified by Na+ channel inactivation at membrane potentials greater than –100 mV (half-maximal inactivation at –49 mV; inset). (F) Q-V relationships in α cells. Data represent average values ± SEM in 8 WT (filled circles) and 4 CaV2.3–/– (shaded circles) α cells. pC, picocoulombs.