When 7 transmembrane receptors are not G protein–coupled receptors
J. Clin. Invest. Keshava Rajagopal, et al. 115:2971 doi:10.1172/JCI26950 [Go to this article.]

Figure 1
An integrated model of signal transduction via the AT1R and resultant physiologic effects within the cardiovascular system. Upon agonist ligand (Ang II) binding to the AT1R, both G protein–dependent and G protein–independent signaling pathways are activated. The AT1R is principally coupled to G_αq, as illustrated, but may also couple to G_αi (not shown). Agonist-induced G_αq activation results in activation of phospholipase C (PLC), which catalyzes breakdown of the membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP₂) into inositol triphosphate (IP₃) and diacylglycerol (DAG), which respectively act to increase cytosolic Ca²⁺ concentrations and to activate PKC. Proximally, a series of events results in the inhibition of initiation of G_αq-mediated signaling (desensitization). Agonist-ligand binding induces GRKs to catalyze cytoplasmic serine/threonine phosphorylation, which enhances binding of β-arrestin to the AT1R cytoplasmic tail; this sterically inhibits G_αq coupling to the AT1R. β-arrestin also serves as a scaffold for signaling effectors such as Src, resulting in downstream activation of cytoplasmic ERK. Also, as illustrated, AT1R induces activation of the JAK/STAT pathway. Upon ligand stimulation, the multifunctional enzyme PI3K is recruited to the plasma membrane by interactions with GRK2 (20). In addition to its protein kinase activity, PI3K functions to catalyze the conversion of PIP₂ to phoshatidylinositol-3,4,5-triphosphate (PIP₃) to promote 7TMR internalization (20). Both G protein–dependent and –independent pathways have distinct physiologic and pathophysiologic effects, as shown. The acute physiologic effects of G protein–independent signaling via AT1R as well as the chronic physiologic effects of G protein–independent signaling on ventricular function and systemic/pulmonary hemodynamics are unknown. The novel physiologic findings of Zhai et al. (3) are each listed and indicated with an asterisk.