A-Kinase Anchoring Proteins (AKAPs) tether cAMP-dependent protein kinase (PKA) to distinc subcellular locations, ensuring efficient activation and accessibility to substrates. AKAPs also bind other signaling components to maintain multicomponent signaling complexes. This proposal focuses on the biological functions dependent upon compartmentalization of secon messenger-regulated signaling enzymes by mAKAP. mAKAP is a recently cloned AKAP that localizes PKA activity to cardiomyocyte nuclear membranes. Due to its chromosomal location, mAKAP is implicated as a candidate gene for familial arrhythmogenic right ventricular dysplasi (ARVD). Other evidence implicates mAKAP in proper heart development and in proper cardiac muscle excitation-contraction (EC) coupling.
Aim 1 proposes to study the scaffolding potential mediated by mAKAP and will test the hypothesis that mAKAP maintains a signaling complex important for cardiomyocyte development and function.
Aim 2 proposes to explore the physiological importance of mAKAP in cardiac function by testing the hypothesis that mA null mice will reveal defects in PKA signaling.
| Michel, Jennifer J Carlisle; Townley, Ian K; Dodge-Kafka, Kimberly L et al. (2005) Spatial restriction of PDK1 activation cascades by anchoring to mAKAPalpha. Mol Cell 20:661-72 |
| Carlisle Michel, Jennifer J; Dodge, Kimberly L; Wong, Wei et al. (2004) PKA-phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signalling complex. Biochem J 381:587-92 |
