|The PKA-AKAP disruptor TAT-AKAD reduces the staining of both PKA-RI and PKA-RII in the nuclear and perinuclear space, respectively (arrows), in cardiac myocytes, suggesting a loss of AKAP-mediated PKA localization.
Proper localization of protein kinase A (PKA) via A-kinase-anchoring proteins (AKAPs) is important for cAMP responsiveness in many cellular systems, including cardiac signaling. In this joint study by the University of California, San Diego, the University of Calgary and Provid Pharmaceuticals, researchers examined the importance of AKAP-mediated targeting of PKA on cardiac function with a specially designed cell-permeable peptide, based on the PKA binding region of AKAP10, called TAT-AKAD (trans-activator of transcription-conjugated A-kinase-anchoring disruptor). After validating PKA interaction, they tested the effects of this peptide in isolated cardiac myocytes and perfused mouse hearts. In myocytes, TAT-AKAD decreased the phosphorylation of phospholamban and troponin I following β-adrenergic stimulation, indicating PKA knockdown; TAT-AKAD treatment also reduced myocyte shortening and the rates of contraction and relaxation. Injecting TAT-AKAD into the coronary circulation of isolated perfused hearts rapidly and reversibly decreased heart rate and left ventricular pressure, and these effects still were seen in hearts pretreated with the β-adrenergic agonist isoproterenol. Together, these results show that disrupted PKA localization produces negative effects on heart rate, contraction and relaxation, confirming that AKAP-targeting of PKA is a vital process for heart function.
Disruption of Protein Kinase A Localization Using a Trans-activator of Transcription (TAT)-conjugated A-kinase-anchoring Peptide Reduces Cardiac Function
Hemal H. Patel, et al.
J. Biol. Chem, published online June 26, 2010
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