The mineralocorticoid receptor (MR) is an aldosterone-regulated transcription factor traditionally associated with sodium and water homeostasis in the kidney and colon. However, recent evidence suggests the MR plays a role in the heart. Studies have found infusion of aldosterone, but not corticosterone, in rats results in cardiac fibrosis and hypertrophy. Administration of the MR antagonist spironolactone, in doses far below those required for regulation of blood pressure, was found to decrease morbidity in patients suffering from cardiac disease. While these studies suggest the MR plays a role in the heart, the mechanism of its action remains undefined. Because there is significant evidence linking mutations in the cardiac myosin binding protein c (cMBP-c) to cardiomyopathies, we propose that interaction between the MR and the cMBP-c may somehow mediate cardiovascular pathways.The goal of this proposal is to characterize the binding of the MR to the cMBP-c and evaluate the effect of this binding on the activity of the MR, with the ultimate aim of understanding the physiological role of the MR within the heart. Experiments will explore the ligand-specific and phosphate-mediated binding of the MR to cMBP-c. Cotransfection studies will determine if the interaction between the two affects the transactivation properties of the MR. Domain swap mutants will determine which area of the MR interacts with the cMBP-c. In addition, site-directed mutagenesis will be used to test the specificity of MR binding to the cardiac isoform of the MBP-c.
| Bratton, Melyssa R; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E et al. (2004) The myosin binding protein is a novel mineralocorticoid receptor binding partner. Mol Cell Endocrinol 217:221-7 |
