| First Author | Guillory AN | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 9 | Pages | e74784 |
| PubMed ID | 24058627 | Mgi Jnum | J:207542 |
| Mgi Id | MGI:5559099 | Doi | 10.1371/journal.pone.0074784 |
| Citation | Guillory AN, et al. (2013) Enhanced cardiac function in Gravin mutant mice involves alterations in the beta-adrenergic receptor signaling cascade. PLoS One 8(9):e74784 |
| abstractText | Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (beta2-AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in beta-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute beta-AR stimulation on cardiac contractility in mice lacking functional gravin. Using echocardiographic analysis, we observed that contractility parameters such as left ventricular fractional shortening and ejection fraction were increased in gravin mutant (gravin-t/t) animals lacking functional protein compared to wild-type (WT) animals both at baseline and following acute isoproterenol (ISO) administration. In isolated gravin-t/t cardiomyocytes, we observed increased cell shortening fraction and decreased intracellular Ca(2+) in response to 1 micromol/L ISO stimulation. These physiological responses occurred in the presence of decreased beta2-AR phosphorylation in gravin-t/t hearts, where PKA-dependent beta2-AR phosphorylation has been shown to lead to receptor desensitization. cAMP production, PKA activity and phosphorylation of phospholamban and troponin I was comparable in WT and gravin-t/t hearts both with and without ISO stimulation. However, cardiac myosin binding protein C (cMyBPC) phosphorylation site at position 273 was significantly increased in gravin-t/t versus WT hearts, in the absence of ISO. Additionally, the cardioprotective heat shock protein 20 (Hsp20) was significantly more phosphorylated in gravin-t/t versus WT hearts, in response to ISO. Our results suggest that disruption of gravin's scaffold mediated signaling is able to increase baseline cardiac function as well as to augment contractility in response to acute beta-AR stimulation by decreasing beta2-AR phosphorylation and thus attenuating receptor desensitization and perhaps by altering PKA localization to increase the phosphorylation of cMyBPC and the nonclassical PKA substrate Hsp20. |
