Compartmentalization of GPCRs

In the heart, Gq-coupled receptors, including α1-adrenergic receptors (α1-ARs), endothelin receptors (ET-Rs), and angiotensin receptors (AT-Rs), mediate hypertrophy, inotropy, and cell survival, and significantly impact heart failure progression. Furthermore, AT-R antagonists are indicated in heart failure. Conversely, α1-AR antagonists have shown no benefit and actually increased mortality in hypertensive patients.

Recently, we demonstrated that α1-ARs exclusively localize to and signal at the nucleus in adult cardiac myocytes, whereas ET-Rs and AT-Rs primarily localize to and signal at the plasma membrane. Furthermore, our previous studies demonstrate that α1-ARs are cardio-protective, whereas ET-Rs and AT-Rs exacerbate pathologic remodeling in the heart. This suggests that localization of a Gq-coupled receptor in cardiac myocytes might dictate it’s ultimate physiologic function: nuclear Gq-receptors are protective, whereas plasma membrane Gq-receptors are pathologic. This represents a significant paradigm shift in how we consider G-protein coupled receptor (GPCR) signaling.

In this project, we are examining how Gq-coupled receptors signal at the nucleus, using α1-ARs as an archetype for other Gq receptors. We are measuring receptor localization/orientation in the nuclear membrane, what other Gq-signaling proteins localize to the nucleus, mechanisms of nuclear targeting, and measuring Gq-receptor signaling at the nucleus in cardiac myocytes. Second, we are examining the physiologic relevance of nuclear Gq-coupled receptor signaling. We are overexpressing a nuclear localized Gαq to determine if increased nuclear Gq signaling is sufficient to protect cardiac myocytes from pathologic stress. Second, we are developing a mis-localized α1-AR to determine if nuclear Gq-signaling is required for protection.