Spinophilin Is Indispensable for the α(2B) Adrenergic Receptor-Elicited Hypertensive Response

The α(2) adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α(2A) subtype elicits a hypotensive response whereas the α(2B) subtype mediates a hypertensive effect that counteracts the hypotensive response by the α(2A) subtype. We have previously shown that spinophilin attenuates the α(2A)AR-dependent hypotensive response; in spinophilin null mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the α(2B)AR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α(2B)AR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 α(2B)AR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining α(2B)AR signaling. Consistent with this notion, our in vivo study reveals that the α(2B)AR-elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the α(2B)AR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α(2A)AR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.