SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells

Lena Eliasson, Xiaosong Ma, Erik Renström, Sebastian Barg, Per Olof Berggren, Juris Galvanovskis, Jesper Gromada, Xingjun Jing, Ingmar Lundquist, Albert Salehi, Sabine Sewing, Patrik Rorsman

Research output: Contribution to journalArticle

206 Scopus citations

Abstract

Measurements of membrane capacitance were applied to dissect the cellular mechanisms underlying PKA-dependent and -independent stimulation of insulin secretion by cyclic AMP. Whereas the PKA-independent (Rp-cAMPS-insensitive) component correlated with a rapid increase in membrane capacitance of ∼80 fF that plateaued within ∼200 ms, the PKA-dependent component became prominent during depolarizations >450 ms. The PKA-dependent and -independent components of cAMP-stimulated exocytosis differed with regard to cAMP concentration dependence; the Kd values were 6 and 29 μM for the PKA-dependent and -independent mechanisms, respectively. The ability of cAMP to elicit exocytosis independently of PKA activation was mimicked by the selective cAMP-GEFII agonist 8CPT-2Me-cAMP. Moreover, treatment of B-cells with antisense oligodeoxynucleotides against cAMP-GEFII resulted in partial (50%) suppression of PKA-independent exocytosis. Surprisingly, B-cells in islets isolated from SUR1-deficient mice (SUR1-/- mice) lacked the PKA-independent component of exocytosis. Measurements of insulin release in response to GLP-1 stimulation in isolated islets from SUR1-/- mice confirmed the complete loss of the PKA-independent component. This was not attributable to a reduced capacity of GLP-1 to elevate intracellular cAMP but instead associated with the inability of cAMP to stimulate influx of Cl- into the granules, a step important for granule priming. We conclude that the role of SUR1 in the B cell extends beyond being a subunit of the plasma membrane KATP-channel and that it also plays an unexpected but important role in the cAMP-dependent regulation of Ca2+-induced exocytosis.

Original languageEnglish (US)
Pages (from-to)181-197
Number of pages17
JournalJournal of General Physiology
Volume121
Issue number3
DOIs
StatePublished - Mar 1 2003

Keywords

  • Ca
  • CAMP
  • CAMP-GEFII
  • Insulin
  • SUR1

ASJC Scopus subject areas

  • Physiology

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    Eliasson, L., Ma, X., Renström, E., Barg, S., Berggren, P. O., Galvanovskis, J., Gromada, J., Jing, X., Lundquist, I., Salehi, A., Sewing, S., & Rorsman, P. (2003). SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic b-cells. Journal of General Physiology, 121(3), 181-197. https://doi.org/10.1085/jgp.20028707