Editors' ChoiceScaffolds

Regulating the Adaptor to Alter cAMP Signaling

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Science's STKE  27 Sep 2005:
Vol. 2005, Issue 303, pp. tw342
DOI: 10.1126/stke.3032005tw342

Although adenosine 3′,5′-monophosphate (cAMP) is a small diffusible second messenger, its activity is localized through the actions of scaffolds such as A kinase anchoring proteins (AKAPs), which interact with protein kinase A (PKA), the major downstream effector of cAMP, and other proteins involved in cAMP signaling. Zhang et al. report the development through protein engineering of a reversible A-kinase reporter protein, AKAR2. This reporter was then used to show that chronic insulin treatment of 3T3-L1 adipocytes led to a delay in the PKA response to the β-adrenergic receptor (β-AR) agonist isoproteronol. This was surprising given that chronic insulin exposure leads to the production of higher concentrations of cAMP in response to β-AR stimulation than those observed in cells not treated with insulin. Activation of the downstream endogenous PKA target CREB (cAMP response element-binding protein) was also delayed. Chronic insulin treatment did not inhibit phosphorylation of AKAR2 by stimuli that bypassed the β-AR, which suggested that PKA was not globally inhibited. Insulin treatment decreased the interaction between β-AR and the regulatory subunit of PKA in response to subsequent exposure to isoproteronol, which suggested that insulin altered the AKAP function, which led to desensitization of the β-AR response. Injection of a peptide that blocked the interaction between AKAP and the regulatory subunit of PKA also blocked activation of the AKAR2 reporter by isoproteronol. These results provide evidence for another mechanism of cross talk between signaling pathways, through disruption of the scaffolding protein functions.

J. Zhang, C. J. Hupfeld, S. S. Taylor, J. M. Olefsky, R. Y. Tsien, Insulin disrupts β-adrenergic signalling to protein kinase A in adipocytes. Nature 437, 569-573 (2005). [Online Journal]

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