α ₂-Adrenoceptors: Challenges and Opportunities—Enlightenment from the Kidney

Figure 2

Signaling mechanisms in the SHR renal microcirculation. Renal sympathetic nerves release norepinephrine which stimulates α₂-adrenoceptors (α₂-ARs) in renal vascular smooth muscle cells, thus leading to dissociation of G_i and release of α_i and βγ subunits. Angiotensin II engages type 1 angiotensin II receptors (AT₁-Rs) which results in the release of α_q from G_q. βγ subunits arising from G_i-coupled α₂-ARs bind receptor for activated C kinase 1 (RACK1) and localize this scaffolding protein to the cell membrane. At the cell membrane, RACK1 also binds phospholipase C (PLC) and protein kinase C (PKC), and PLC binds α_q. Together, these interactions result in an efficient signaling complex in which activation of PLC by α_q is enhanced by the simultaneous binding of βγ subunits to PLC. Thus, PLC serves as a coincident detector, whereas RACK1 functions here to bring together the stimulating components of this coincident signaling mechanism. This coincident signaling mechanism is further amplified by the fact that RACK1 localizes PLC with PKC, thus facilitating the activation of PKC, which mediates contraction of vascular smooth muscle cells. In addition to βγ-mediated signaling, release of α_i by α₂-ARs inhibits the adenylate cyclase/cAMP pathway, which further increases contraction of vascular smooth muscle cells. Because of the increased pool of G_i-coupled α₂-ARs, both the α_i-mediated and βγ-mediated mechanisms are more engaged in the SHR renal microvasculature, thus leading to renal vasoconstriction, sodium retention, and hypertension. The model was tested using pressor levels of angiotensin II with renovascular responses (or in some experiments contractile responses to isolated preglomerular vascular smooth muscle cells) as the outcome measure and, therefore, applies to sympathetic regulation of renal vascular smooth muscle cells; however, we hypothesize that similar coincident signaling involving α₂-ARs may occur in renal epithelial cells and may contribute directly to sodium retention and hypertension independent of renovascular changes.