Nature 439, 349-352 (19 January 2006) | doi:10.1038/nature04410; Received 26 July 2005; Accepted 8 November 2005

Oscillations of cyclic AMP in hormone-stimulated insulin-secreting bold beta-cells

Oleg Dyachok1,2, Yegor Isakov1, Jenny Sågetorp1 & Anders Tengholm1

  1. Department of Medical Cell Biology, Uppsala University, BMC, Box 571, SE-751 23 Uppsala, Sweden
  2. Department of Biophysics, Kiev T. Shevchenko National University, 01033 Kiev, Ukraine

Correspondence to: Anders Tengholm1 Correspondence and requests for materials should be addressed to A.T. (Email: anders.tengholm@medcellbiol.uu.se).

Cyclic AMP is a ubiquitous second messenger that transduces signals from a variety of cell surface receptors to regulate diverse cellular functions, including secretion, metabolism and gene transcription. In pancreatic beta-cells, cAMP potentiates Ca2+-dependent exocytosis1, 2, 3 and mediates the stimulation of insulin release exerted by the hormones glucagon and glucagon-like peptide-1 (GLP-1) (refs 4 , 5 –6). Whereas Ca2+ signals have been extensively characterized and shown to involve oscillations important for the temporal control of insulin secretion4, 7, 8, the kinetics of receptor-triggered cAMP signals is unknown. Here we introduce a new ratiometric evanescent-wave-microscopy approach to measure cAMP concentration beneath the plasma membrane, and show that insulin-secreting beta-cells respond to glucagon and GLP-1 with marked cAMP oscillations. Simultaneous measurements of intracellular Ca2+ concentration revealed that the two messengers are interlinked and reinforce each other. Moreover, cAMP oscillations are capable of inducing rapid on–off Ca2+ responses, but only sustained elevation of cAMP concentration induces nuclear translocation of the catalytic subunit of the cAMP-dependent protein kinase. Our results establish a new signalling mode for cAMP and indicate that temporal encoding of cAMP signals might constitute a basis for differential regulation of downstream cellular targets.