Identification of α 1L ‐adrenoceptor in mice and its abolition by α 1A ‐adrenoceptor gene knockout

Background and purpose: The α 1L ‐adrenoceptor has pharmacological properties that distinguish it from three classical α 1 ‐adrenoceptors (α 1A , α 1B and α 1D ). The purpose of this was to identify α 1L ‐adrenoceptors in mice and to examine their relationship to classical α 1 ‐adrenoceptors. Experimental approach: Radioligand binding and functional bioassay experiments were performed on the cerebral cortex, vas deferens and prostate of wild‐type (WT) and α 1A ‐, α 1B ‐ and α 1D ‐adrenoceptor gene knockout (AKO, BKO and DKO) mice. Key results: The radioligand [ 3 H]‐silodosin bound to intact segments of the cerebral cortex, vas deferens and prostate of WT, BKO and DKO but not of AKO mice. The binding sites were composed of two components with high and low affinities for prazosin or RS‐17053, indicating the pharmacological profiles of α 1A ‐adrenoceptors and α 1L ‐adrenoceptors. In membrane preparations of WT mouse cortex, however, [ 3 H]‐silodosin bound to a single population of prazosin high‐affinity sites, suggesting the presence of α 1A ‐adrenoceptors alone. In contrast, [ 3 H]‐prazosin bound to two components having α 1A ‐adrenoceptor and α 1B ‐adrenoceptor profiles in intact segments of WT and DKO mouse cortices, but AKO mice lacked α 1A ‐adrenoceptor profiles and BKO mice lacked α 1B ‐adrenoceptor profiles. Noradrenaline produced contractions through α 1L ‐adrenoceptors with low affinity for prazosin in the vas deferens and prostate of WT, BKO and DKO mice. However, the contractions were abolished or markedly attenuated in AKO mice. Conclusions and implications: α 1L ‐Adrenoceptors were identified as binding and functional entities in WT, BKO and DKO mice but not in AKO mice, suggesting that the α 1L ‐adrenoceptor is one phenotype derived from the α 1A ‐adrenoceptor gene. British Journal of Pharmacology (2008) 155 , 1224–1234; doi: 10.1038/bjp.2008.360 ; published online 22 September 2008