Hypnotic and Hypotensive Responses to the Alpha2‐adrenergic Agonists Are Enhanced and Accompanied by Increased G Protein Coupling to the Alpha2AAR in Spinophilin Null Mice

We have previously identified spinophilin (SP) as a critical regulator of alpha2 adrenergic receptor trafficking and signaling both in vitro and in vivo. Compared to wild type mice, mice lacking SP expression are more sensitive to alpha2‐agonist‐elicited sedation. In the present study, we assessed cardiovascular responses and hypnotic effects elicited by systemic administration of an alpha2‐agonist, UK14,304, in SP null mice. Our data demonstrate that mice lacking SP expression display dramatically enhanced and prolonged hypotensive, bradycardic, and hypnotic responses to alpha2AAR stimulation. These changes in sensitivity to alpha2AR agonist occur independent of any changes in alpha2AAR density or intrinsic affinity for UK14,304 in the brain of SP null mice when compared to wild type controls. In contrast, the data indicate that coupling of the alpha2AAR to cognate G proteins is enhanced in SP null mice, based on changes in guanine nucleotide regulation of UK14,304 binding and evidence of a larger fraction of alpha2AAR in the high affinity state in preparations from SP null mice when compared to those from wild type mice. This suggests that an enhanced receptor/G protein coupling efficiency in the absence of SP expression contribute to an increased responsiveness of alpha2AARs in SP null mice, indicating that SP may exert ongoing regulation of receptor‐G protein coupling in vivo.