Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal via G protein–independent mechanisms. However, the physiologic consequences of this unconventional signaling, particularly in vivo, have not been explored. In this issue of the JCI, Zhai et al. demonstrate in vivo effects of G protein–independent signaling by the angiotensin II type 1 receptor (AT1R). In studies of the mouse heart, they compare the physiologic and biochemical consequences of transgenic cardiac-specific overexpression of a mutant AT1R incapable of G protein coupling with those of a wild-type receptor. Their results not only provide the first glimpse of the physiologic effects of this newly appreciated mode of signaling but also provide important and previously unappreciated clues as to the underlying molecular mechanisms.

All vital physiologic functions of higher-order animals are critically regulated by signal transduction through 7 transmembrane receptors (7TMRs), which in the in vivo context has traditionally been understood to be mediated via heterotrimeric G proteins and downstream second-messenger molecules (1). However, for a number of years, biochemical and cellular studies have suggested that some aspects of 7TMR-mediated signaling apparently occur independently of G protein activation (2). Yet, the physiologic and/or pathophysiologic roles that such novel mechanisms of signal transduction play in vivo are unknown.