Agonist‐dependent responses at central alpha2A adrenergic receptors are regulated by spinophilin

In the present study, we have set out to examine the role of the dendritic scaffolding protein spinophilin (Sp) in regulating agonist‐dependent α 2A adrenergic receptor (α 2A AR) responses in native central neurons, an important locus for α 2A AR endogenous function and therapeutic targeting. We have made use of a powerful tool, HA‐tagged α 2A AR knock‐in mice, which allow for specific examination of the α 2A AR subtype at endogenous expression levels in native cells. These mice have been crossed with Sp‐null animals, allowing for the study of endogenous α 2A ARs in systems wild‐type (WT) and null for Sp expression. Responses to clonidine at the cellular level were found to be altered in Sp‐null native neurons in vitro , specifically with altered profiles of agonist‐induced α 2A AR trafficking and signaling. At the in vivo level, Sp‐null mice were more sensitive to clonidine‐evoked sedation, indicating that this regulation occurs in the intact central nervous system. This regulation by Sp was not observed for another α 2 AR agonist, guanfacine, indicating ligand‐selectivity for Sp‐mediated regulation of the α 2A AR. Our results suggest that this mode of regulation by Sp has a major influence on the neuropharmacology of a clinically‐relevant therapeutic α 2A AR ligand. Work supported by NIH grant MH081917 (QW) and the UAB Training Program in Neurobiology of Cognition and Cognitive Disorders funded by NIH grant NS061788‐03 (CC).