G-Protein Coupled Receptors (GPCRs) comprise a relatively large portion of the human genome (~5% of all transcripts in the genome), and signaling between GPCRs, small G proteins, and various downstream effectors is controlled by Regulator of G-protein Signaling (RGS) proteins. RGS proteins function to return an active G-alpha protein (G-alpha-GTP) to its inactive yet primed state (G-alpha-GDP). it has been established that the function and expression of G proteins and GPCRs are affected by disease. We are interested in examining the role of RGS proteins in regulating cardiovascular development, remodeling, and disease. While other RGS family members have been determined to play a role in the cardiovascular system and hypertension. RGS5 is the predominate RGS protein, expressed in vascular smooth muscle cells (vSMCs). Our preliminary results demonstrate that differential RGS5 expression (as well as expression of the closely related RGS-R4 subfamily) identifies specific vascular segments and may regulate a vessel's response to injury. Furthermore, the ability of a vSMC to undergo hypertrophy is dependent upon the presence of RGS5. Finally, blood pressure appears to be dependent upon the presence of RGS5 in vivo. Taken together, we hypothesize RGS5 may represent a critical and key protein lo understanding hypertension and additional cardiovascular-related diseases. The experiments described will (1) characterize the transcriptional regulatory mechanism controlling RGS5 mRNA expression in vitro;(2) characterize the RGS5 promoter in vivo: (3) investigate the activity of RGS5 during development and in response to vascular injury;(4) use the RGS6 promoter as a molecular model to address larger pathophysiologic question ,focusing on the likely hypothesis that functional adaptation of arteries determined by the coordinate control mechanism for transcription of mRNA for protein s that are the key differential arterial function.
Regulator of G-protein signaling (RGS) proteins control signaling through GPCRs and their downstream Mediators. These experiments will further characterize RGS5, a gene which identifies specific arterial beds, and correlate its expression with blood pressure regulation and the control of arterial remodeling in response to vascular injury.
