Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 30 April 2013
Vol. 6, Issue 273, p. ra29
[DOI: 10.1126/scisignal.2003932]

RESEARCH ARTICLES

Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic β Cells

Olof Idevall-Hagren, Ida Jakobsson, Yunjian Xu, and Anders Tengholm*

Department of Medical Cell Biology, Uppsala University, Biomedical Centre, Box 571, SE-751 23 Uppsala, Sweden.

Abstract: The cAMP (adenosine 3',5'-monophosphate)–activated guanine nucleotide exchange factor (GEF) Epac2 is an important mediator of cAMP-dependent processes in multiple cell types. We used real-time confocal and total internal reflection fluorescence microscopy to examine the spatiotemporal regulation of Epac2, which is a GEF for the guanosine triphosphatase (GTPase) Rap. We demonstrated that increases in the concentration of cAMP triggered the translocation of Epac2 from the cytoplasm to the plasma membrane in insulin-secreting β cells. Glucose-induced oscillations of the submembrane concentration of cAMP were associated with cyclic translocation of Epac2, and this translocation could be amplified by increases in the cytoplasmic Ca2+ concentration. Analyses of Epac2 mutants identified the high-affinity cAMP-binding and the Ras association domains as crucial for the translocation. Expression of a dominant-negative Ras mutant reduced Epac2 translocation, and Ca2+-dependent oscillations in Ras activity synchronized with Epac2 translocation in single β cells. The cyclic translocation of Epac2 was accompanied by oscillations of Rap GTPase activity at the plasma membrane, and expression of an inactive Rap1B mutant decreased insulin secretion. Thus, Epac2 localization is dynamically controlled by cAMP as well as by Ca2+-mediated activation of Ras. These results help to explain how oscillating signals can produce pulses of insulin release from pancreatic β cells.

* Corresponding author. E-mail: anders.tengholm{at}mcb.uu.se

Citation: O. Idevall-Hagren, I. Jakobsson, Y. Xu, A. Tengholm, Spatial Control of Epac2 Activity by cAMP and Ca2+-Mediated Activation of Ras in Pancreatic β Cells. Sci. Signal. 6, ra29 (2013).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Antidiabetic Sulfonylureas and cAMP Cooperatively Activate Epac2A.
T. Takahashi, T. Shibasaki, H. Takahashi, K. Sugawara, A. Ono, N. Inoue, T. Furuya, and S. Seino (2013)
Science Signaling 6, ra94
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882