We previously identified spinophilin as a regulator of ␣ 2 adrenergic receptor (␣ 2 AR) trafficking and signaling in vitro and in vivo (Science 304:1940(Science 304: -1944(Science 304: , 2004. To assess the generalized role of spinophilin in regulating ␣ 2 AR functions in vivo, the present study examined the impact of eliminating spinophilin on ␣ 2 AR-evoked cardiovascular and hypnotic responses, previously demonstrated to be mediated by the ␣ 2A AR subtype, after systemic administration of the ␣ 2 -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 ␣ 2 AR stimulation. Whereas these changes in sensitivity to ␣ 2 AR agonists occur independent of any changes in ␣ 2A AR density or intrinsic affinity for agonist in the brains of spinophilin-null mice compared with wild-type control mice, the coupling of the ␣ 2A 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 ␣ 2A 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.The ␣ 2 -adrenergic receptor (AR) is a prototypical G protein-coupled receptor (GPCR) that couples to the G i/o subfamily of G proteins (Wang and Limbird, 2007). In native cells, stimulation of the ␣ 2 AR leads to inhibition of adenylyl cyclase and voltage-gated Ca 2ϩ currents and to activation of receptor-operated K ϩ currents and mitogen activated protein kinase (
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