Discovery of AKAP Function

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Historically, most AKAPs were initially identified in screens for PKA-binding proteins. Thus, these AKAPs tend to be better characterized. The function and/or identity of many other putative AKAPs, however, remains obscure. For cellular processes where it has been suspected that PKA anchoring may be involved, techniques to globally disrupt PKA anchoring in a cell have proven quite useful. A peptide that mimics the Rll-binding domain of AKAP-Lbc (termed Ht31 peptide) competes with AKAP/PKA binding both in vivo and in vitro (Carr et al. 1992). Over-expression of this peptide has been used to demonstrate the importance of PKA anchoring for several physiological functions (Rosenmund et al. 1994).

The use of the Ht31 peptide demonstrated the importance of AKAPs in non-insulin-dependent diabetes mellitus (NIDDM) (Lester et al. 1997). Over-expression of the anchoring inhibitor peptide in primary islets and cloned beta cell lines blocked the ability of the hormone glucagon-like peptide (GLP-1) to stimulate insulin secretion. Furthermore, expression of Ht31 in these cells disrupted cAMP-mediated increases in intracellular calcium. These data suggest that an anchored pool of PKA regulates both insulin secretion and calcium flux in these cells.

In another example of the importance of AKAPs, Fink et al. (2001) used adenoviral-mediated expression of the Ht31 peptide in cardiac myocytes. Global inhibition of PKA anchoring in myocytes resulted in an increased rate and amplitude of cell shortening and relaxation. Furthermore, Ht31 expression blocked PKA phosphor-ylation of troponin I and myosin-binding protein C, suggesting that AKAP-bound PKA regulates the phosphorylation of these targets. Both of these examples highlight the dependence of proper physiological function on anchored PKA signaling. Thus, screens to identify other unknown AKAPs and the physiological pathways they mediate are warranted.

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