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¹ Department of Pharmacology and ² Tri-instutional MD/PhD Program, Weill Medical College of Cornell University, New York, NY 10065

Correspondence to Jochen Buck: jobuck{at}med.cornell.edu

In β cells, both glucose and hormones, such as GLP-1, stimulate production of the second messenger cAMP, but glucose and GLP-1 elicit distinct cellular responses. We now show in INS-1E insulinoma cells that glucose and GLP-1 produce cAMP with distinct kinetics via different adenylyl cyclases. GLP-1 induces a rapid cAMP signal mediated by G protein–responsive transmembrane adenylyl cyclases (tmAC). In contrast, glucose elicits a delayed cAMP rise mediated by bicarbonate, calcium, and ATP-sensitive soluble adenylyl cyclase (sAC). This glucose-induced, sAC-dependent cAMP rise is dependent upon calcium influx and is responsible for the glucose-induced activation of the mitogen-activated protein kinase (ERK1/2) pathway. These results demonstrate that sAC-generated and tmAC-generated cAMP define distinct signaling cascades.

J.H. Zippin's present address is Department of Dermatology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065.

Abbreviations used in this paper: 2'5' ddAdo, 2'5' dideoxyadenosine; ERK1/2, extracellular signal-regulated kinases 1 and 2; GPCR, G protein–coupled receptor; IBMX, 3-isobutyl-1-methylxanthine; MAP, mitogen-activated protein; PDE, phosphodiesterase; sAC, soluble adenylyl cyclase; tmAC, transmembrane adenylyl cyclase.

© 2008 Ramos et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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