Regulation of L-type Ca2+ channel activity and insulin secretion by the Rem2 GTPase

Brian S. Finlin, Amber L. Mosley, Shawn M. Crump, Robert N. Correll, Sabire Özcan, Jonathan Satin, Douglas A. Andres

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Abstract

Voltage-dependent calcium (Ca2+) channels are involved in many specialized cellular functions and are controlled by a diversity of intracellular signals. Recently, members of the RGK family of small GTPases (Rem, Rem2, Rad, Gem/Kir) have been identified as novel contributors to the regulation of L-type calcium channel activity. In this study, microarray analysis of the mouse insulinoma MIN6 cell line revealed that the transcription of Rem2 gene is strongly induced by exposure to high glucose, which was confirmed by real-time reverse transcriptase-PCR and RNase protection analysis. Because elevation of intracellular Ca2+ in pancreatic β-cells is essential for insulin secretion, we tested the hypothesis that Rem2 attenuates Ca2+ currents to regulate insulin secretion. Co-expression of Rem2 with Cav1.2 or Cav1.3 L-type Ca2+ channels in a heterologous expression system completely inhibits de novo Ca2+ current expression. In addition, ectopic overexpression of Rem2 both inhibited L-type Ca2+ channel activity and prevented glucose-stimulated insulin secretion in pancreatic β-cell lines. Co-immunoprecipitation studies demonstrate that Rem2 associates with a variety of Cavβ subunits. Importantly, surface biotinylation studies dem-onstrate that the membrane distribution of Ca2+ channels was not reduced at a time when channel activity was potently inhibited by Rem2 expression, indicating that Rem2 modulates channel function without interfering with membrane trafficking. Taken together, these data suggest that inhibition of L-type Ca2+ channels by Rem2 signaling may represent a new and potentially important mechanism for regulating Ca2+-triggered exocytosis in hormone-secreting cells, including insulin secretion in pancreatic β-cells.

Original languageEnglish (US)
Pages (from-to)41864-41871
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number51
DOIs
StatePublished - Dec 23 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Finlin, B. S., Mosley, A. L., Crump, S. M., Correll, R. N., Özcan, S., Satin, J., & Andres, D. A. (2005). Regulation of L-type Ca2+ channel activity and insulin secretion by the Rem2 GTPase. Journal of Biological Chemistry, 280(51), 41864-41871. https://doi.org/10.1074/jbc.M414261200