%0 Journal Article %A Roujian Lu %A Yunjia Chen %A Christopher Cottingham %A Ning Peng %A Kai Jiao %A Lee E Limbird %A J Michael Wyss %A Qin Wang %T Enhanced Hypotensive, Bradycardia and Hypnotic Responses to α2-adrenergic Agonists in Spinophilin Null Mice Are Accompanied by Increased G Protein Coupling to the α2AAR %D 2010 %R 10.1124/mol.110.065300 %J Molecular Pharmacology %P mol.110.065300 %X We previously identified spinophilin as a regulator of α2 adrenergic receptor (α2AR) trafficking and signaling in vitro and in vivo (Wang Q., Zhao J., Brady A.E., Feng J., Allen P.B., Lefkowitz R.J., Greengard P. and Limbird L.E. (2004) Science 304, 1940-1944). To assess the generalized role of spinophilin in regulating α2AR functions in vivo, the present study examined the impact of eliminating spinophilin on α2AR-evoked cardiovascular and hypnotic responses, previously demonstrated to be mediated by the α2AAR subtype, following systemic administration of the α2-agonists, UK14,304 and clonidine, in spinophilin null mice. Mice lacking spinophilin expression display dramatically enhanced and prolonged hypotensive, bradycardic as well as sedative-hypnotic responses to α2AR stimulation. Whereas these changes in sensitivity to α2AR agonists occur independent of any changes in α2AAR density or intrinsic affinity for agonist in the brain of spinophilin null mice when compared to wild type controls, the coupling of the α2AAR 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 α2AAR in the guanine-nucleotide-sensitive higher affinity state when compared to 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.The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/early/2010/04/29/mol.110.065300.full.pdf