Cyclic GMP kinase I modulates glucagon release from pancreatic α-cells

  1. Robert Lukowski (robert.lukowski{at},5
  1. 1FOR 923, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, D-81377 München, Germany
  2. 2Institut für Pharmakologie und Toxikologie, Abteilung Pharmakologie und Experimentelle Therapie, Universitätsklinikum Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany
  3. 3Lehrstuhl für Physiologie I, Julius-Maximilians Universität Würzburg, Röntgenring 9, D-97070 Würzburg, Germany
  4. 4Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteiner Str. 29, D-80802 München, Germany
  5. 5Institut für Pharmazie, Abteilung Pharmakologie, Toxikologie und Klinische Pharmazie, Universität Tübingen, Auf der Morgenstelle 8, D-72076 Tübingen, Germany


Objective: The physiological significance of the nitric oxide (NO)/cGMP signaling pathway in islets is unclear. We hypothesized that cGMP-dependent protein kinase type I (cGKI) is directly involved in the secretion of islet hormones and glucose homeostasis.

Research design and methods: Gene-targeted mice that lack cGKI in islets (conventional cGKI mutants and cGKIα and Iβ rescue mice (α/βRM) that express cGKI only in smooth muscle) were studied in comparison to control (CTR) mice. cGKI expression was mapped in the endocrine pancreas by Western blot, immuno-histochemistry, and islet-specific recombination analysis. Insulin, glucagon secretion and cytosolic Ca2+ ([Ca2+]i) were assayed by RIA and FURA-2 measurements, respectively. Serum levels of islet hormones were analyzed at fasting and upon glucose challenge (2 g/kg) in vivo.

Results: Immuno-histochemistry showed that cGKI is present in α- but not in β-cells in islets of Langerhans. Mice that lack α-cell cGKI had significantly elevated fasting glucose and glucagon levels, whereas serum insulin levels were unchanged. High glucose concentrations strongly suppressed the glucagon release in CTR mice but had only a moderate effect on islets that lacked cGKI. 8-Br-cGMP reduced stimulated [Ca2+]i levels and glucagon release rates of CTR islets at 0.5 mM glucose, but was without effect on [Ca2+]i or hormone release in cGKI-deficient islets.

Conclusions: We propose that cGKI modulates glucagon release by suppression of [Ca2+]i in α-cells.

  • Received April 27, 2010.
  • Accepted October 7, 2010.