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SUR1 Regulates PKA-independent cAMP-induced Granule Priming in Mouse Pancreatic B-cells
2 The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
3 Lilly Research Laboratories, D-22419 Hamburg, Germany
Address correspondence to Patrik Rorsman, Department of Molecular and Cellular Physiology, Institute of Physiological Sciences, BMC F11, SE-221 84 Lund, Sweden. Fax: (46) 46-2227763; E-mail: patrik.rorsman{at}mphy.lu.se
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.
Key Words: insulin • Ca2+ • cAMP • cAMP-GEFII • SUR1
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