Figure 8. Schematic illustration of angiotensin II type 1a receptor (AT1aR) biased signaling cascade regulating myogenic arterial tone.

Canonical G_q/11 signaling pathway of the AT1R (purple blue) causes myogenic vasoconstriction whereas noncanonical β‐arrestin‐biased signaling is not involved in this process. G_q/11 proteins are heterotrimeric G proteins, which are made up of alpha (α), beta (β), and gamma (γ) subunits. The alpha subunit is attached to either a guanosine triphosphate (GTP) or guanosine diphosphate (GDP), which serves as an on‐off switch for the activation of the G‐protein. Upon activation of the AT1aR by either ligand‐independent mechanical stretch or the natural‐biased ligand Ang II, the Gβγ complex is released from the Gα subunit after its GDP‐GTP exchange for canonical G protein signaling to cause myogenic and/or humoral (Ang II‐mediated) vasoconstriction. This pathway is inhibited by the G_q/11 inhibitor FR900359. Although, GRKs and arrestins play a role in multiple noncanonical signaling pathways in cells, this pathway is unlikely engaged by mechanoactivated AT1Rs in response to tensile stretch or their natural ligand angiotensin II to cause vasoconstriction. Ang II indicates angiotensin II; GRK, G protein‐coupled receptor kinase; and SII, Sar1Ile4Ile8‐angiotensin.