Enhanced hypotensive, bradycardic, and hypnotic responses to α2-adrenergic agonists in spinophilin-null mice are accompanied by increased G protein coupling to the α2A-adrenergic receptor

Academic Article

Abstract

  • We previously identified spinophilin as a regulator of α adrenergic receptor (α AR) trafficking and signaling in vitro and in vivo (Science 304:1940-1944, 2004). To assess the generalized role of spinophilin in regulating α AR functions in vivo, the present study examined the impact of eliminating spinophilin on α AR- evoked cardiovascular and hypnotic responses, previously demonstrated to be mediated by the α AR subtype, after systemic administration of the α -agonists 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6- quinoxalinamine (UK14,304) and clonidine in spinophilin-null mice. Mice lacking spinophilin expression display dramatically enhanced and prolonged hypotensive, bradycardic, and sedative-hypnotic responses to α AR stimulation. Whereas these changes in sensitivity to α AR agonists occur independent of any changes in α AR density or intrinsic affinity for agonist in the brains of spinophilin-null mice compared with wild-type control mice, the coupling of the α AR to cognate G proteins is enhanced in spinophilin-null mice. Thus, brain preparations from spinophilin-null mice demonstrate enhanced guanine nucleotide regulation of UK14,304 binding and evidence of a larger fraction of α AR in the guanine-nucleotide-sensitive higher affinity state compared with those from wild-type mice. These findings suggest that eliminating spinophilin expression in native tissues leads to an enhanced receptor/G protein coupling efficiency that contributes to sensitization of receptor mediated responses in vivo. Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics. 2 2 2 2 2A 2 2 2 2A 2A 2A
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    Author List

  • Lu R; Chen Y; Cottingham C; Peng N; Jiao K; Limbird LE; Wyss JM; Wang Q
  • Start Page

  • 279
  • End Page

  • 286
  • Volume

  • 78
  • Issue

  • 2