cAMP is an important second messenger that regulates several physiological events in the heart including contraction, metabolism and gene transcription. Several recent studies have illustrated not only the importance of phosphodiesterases (PDE) for the control of basal cAMP levels in the heart, but also in the regulation of localized changes of cAMP due to the cellular location of PDEs. Therefore, identifying the molecular determinants governing PDE localization and activity, as well as the biological processes attributed to each PDE, will further our knowledge of cAMP signaling in the heart. We have previously described a scaffolding protein that sequesters the phosphodiesterase PDE4D3 to the nuclear envelope in differentiated cardiac myocytes. The A-Kinase Anchoring Protein mAKAP maintains a complex consisting of the cAMP-dependent protein kinase, PDE4D3, the Map Kinase ERK5, the guanine nucleotide exchange factor Epac, the protein phosphatase 2A, and the Ryanodine Receptor. Previous data has shown mAKAP orchestrated both ERK5 and PKA regulation of PDE4D3. These phosphorylation-induced changes in PDE4D3 activity will in turn modulate the concentration of cAMP surrounding the complex, ultimately regulating all cAMP effectors in the complex, namely PKA, PDE4D3 and Epac. The three Specific Aims of this proposal will try to 1) elucidate the physiological events that regulate PDE4D3 phosphorylation regulate cAMP concentration and the phosphorylation state of the Ryanodine Receptor 2) determine the functional consequence of PDE4D3 phosphorylation on Epac-mediated ERK5 activity and ERK5-mediated cardiac hypertrophy, and 3) identify the phosphatase in the complex that governs dephosphorylation of the PDE. Heart disease is the number one cause of death in the United States. Cardiac hypertrophy is the major compensatory mechanism by which the heart responds to a continued, increased demand for cardiac output. Ultimately, cardiac hypertrophy leads to progression into cardiac disease and to heart failure. However, several studies have shown that inhibition of cardiac hypertrophy lowers the risk of death and progression into heart failure. This study will further our understanding of the molecular mechanism of cardiac hypertrophy and help to identify novel targets for drug design to aid in the treatment of hypertrophy. ? ? ?
| Rigatti, Marc; Le, Andrew V; Gerber, Claire et al. (2015) Phosphorylation state-dependent interaction between AKAP7?/? and phospholamban increases phospholamban phosphorylation. Cell Signal 27:1807-15 |
| Greenwald, Eric C; Redden, John M; Dodge-Kafka, Kimberly L et al. (2014) Scaffold state switching amplifies, accelerates, and insulates protein kinase C signaling. J Biol Chem 289:2353-60 |
| Kapiloff, Michael S; Rigatti, Marc; Dodge-Kafka, Kimberly L (2014) Architectural and functional roles of A kinase-anchoring proteins in cAMP microdomains. J Gen Physiol 143:9-15 |
| Li, Jinliang; Kritzer, Michael D; Michel, Jennifer J Carlisle et al. (2013) Anchored p90 ribosomal S6 kinase 3 is required for cardiac myocyte hypertrophy. Circ Res 112:128-39 |
| Li, Jinliang; Vargas, Maximilian A X; Kapiloff, Michael S et al. (2013) Regulation of MEF2 transcriptional activity by calcineurin/mAKAP complexes. Exp Cell Res 319:447-54 |
| Vargas, Maximilian A X; Tirnauer, Jennifer S; Glidden, Nicole et al. (2012) Myocyte enhancer factor 2 (MEF2) tethering to muscle selective A-kinase anchoring protein (mAKAP) is necessary for myogenic differentiation. Cell Signal 24:1496-503 |
| Redden, John M; Le, Andrew V; Singh, Arpita et al. (2012) Spatiotemporal regulation of PKC via interactions with AKAP7 isoforms. Biochem J 446:301-9 |
| Mian, Isma; Pierre-Louis, Willythssa Stephie; Dole, Neha et al. (2012) LKB1 destabilizes microtubules in myoblasts and contributes to myoblast differentiation. PLoS One 7:e31583 |
| Kritzer, Michael D; Li, Jinliang; Dodge-Kafka, Kimberly et al. (2012) AKAPs: the architectural underpinnings of local cAMP signaling. J Mol Cell Cardiol 52:351-8 |
| Diviani, Dario; Dodge-Kafka, Kimberly L; Li, Jinliang et al. (2011) A-kinase anchoring proteins: scaffolding proteins in the heart. Am J Physiol Heart Circ Physiol 301:H1742-53 |
Showing the most recent 10 out of 16 publications
