Future Directions

Although the second messenger cAMP and its major target PKA have been extensively studied, the idea that localized domains of cAMP result in the discrete activation of select pools of PKA is still relatively novel. Multiple lines of research have implicated the role of AKAPs in providing the molecular architecture of these microdomains. However, the analysis of the physiological significance of AKAPs is still incomplete. Undoubtedly, this field will benefit from genetic approaches utilizing knockout mice of the various AKAPs. These studies should not only provide insight into the molecular mechanisms of AKAP function, but also into the physiological roles of the different AKAP scaffolds. In particular, AKAP knock-out mice will be useful in determining whether individual AKAPs are potential targets for therapeutic intervention. These studies will complement existing information using the Ht31 peptide to globally disrupt PKA anchoring in a multitude of cells.

The paradox seen in the heart that cAMP can lead to both "good" and "bad" outcomes highlights the importance of cAMP micodomains and the ability of the cell to main these domains under stress conditions. Thus, one can imagine restoring the balance of cAMP signaling by modulating these localized domains. AKAPs would provide an ideal mechanism for the management of cAMP microdomains and may provide novel therapeutic strategies against heart failure. However, to utilize this approach would require an in-depth analysis of AKAP targets and their phoshorylation status in the heart disease.

The disadvantage of targeting PKA/AKAP interactions is that all known inhibitory reagents are not specific for a particular AKAP. Therefore, the development of anchoring inhibitory peptides that affect only one specific AKAP would be of great interest. For example, Alto et al. (2003) used both computer-based modeling and peptide-array analysis to design a peptide that is 10,000-fold more selective for disrupting AKAP/RII interactions over RI. Importantly, the complete understanding of the AKAP complex and its role in the regulation of cell biology will allow for the design of novel drugs, providing potential therapeutic strategies for the treatment and management of many diseases.

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