Spinophilin is indispensable for the α2B adrenergic receptor-elicited hypertensive response

Academic Article

Abstract

  • The α adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α subtype elicits a hypotensive response whereas the α subtype mediates a hypertensive effect that counteracts the hypotensive response by the α subtype. We have previously shown that spinophilin attenuates the α 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 AR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α 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 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 AR signaling. Consistent with this notion, our in vivo study reveals that the α 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 AR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α 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. 2 2A 2B 2A 2A 2B 2B 2B 2B 2B 2B 2A
  • Published In

  • PLoS ONE  Journal
  • Digital Object Identifier (doi)

    Author List

  • Che P; Chen Y; Lu R; Peng N; Gannon M; Wyss JM; Jiao K; Wang Q
  • Volume

  • 10
  • Issue

  • 8