Alpha1-adrenoceptor subtype substitution in knockout mice.

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Since the discovery of α1-adrenoceptor subtypes, there has been continued interest in the identification of their functional roles. This has been facilitated by the availability of increasingly selective antagonists for individual subtypes, especially for the α1A and α1D, as well as knockout (KO) mice lacking either α1A, α1B or α1D adrenoceptors (Hague et al., 2003). In some tissues, such as heart or blood vessels, multiple α1 subtypes are present and produce the same functional response, although the dominant subtype can vary between species or particular blood vessels (Hrometz et al., 1999). In other cases, such as in most urogenital smooth muscles, the response is mediated primarily by a single subtype (α1A) independent of species (Ruffolo & Hieble, 1999). Depending on the species, the dominant α1-adrenoceptor mediating metabolic responses in the liver is either α1A (human, cat, dog, rabbit) or α1B (rat, mouse, hamster). In the monkey, hepatic α1A and α1B adrenoceptors both contribute (Garcia-Sainz et al., 1996). In this issue of British Journal of Pharmacology, Deighan et al. (2004) show that, in α1B KO mice, the function of the hepatic α1B adrenoceptor can be assumed by the α1A. Radioligand-binding assays show RS100329, a selective α1A antagonist, to have 30-fold greater affinity for α1-adrenoceptors in hepatocytes from the KO animals (pKi=9.3) than in WT animals (pKi=7.8). In contrast, the selective α1D antagonist BMY 7378 had low affinity in both WT and KO mice (pKi=6.3 and 6.2, respectively). At 4 months of age, the liver from α1B KO mice had a substantial α1-receptor binding (30 fmol mg−1 protein), although less than WT mice of the same age (50 fmol mg−1 protein). However, 3-month-old KO mice had almost no hepatic α1-adrenoceptor binding. This would indicate that replacement of the missing α1B adrenoceptor by the α1A is a relatively slow process, and suggest that, in general, comparisons of receptor density between WT and KO mice should be made at multiple time points. Based on multiple literature reports, it is now clear that α1-adrenoceptors are not confined to the cell membrane, and that the subcellular localization can differ between subtypes (Mackenzie et al., 2000; Stanasila et al., 2003; Hague et al., 2004). Deighan et al. (2004) show that the distribution of α1A adrenoceptors in KO mice is identical to that of the α1B in WT mice, consistent with the ability of the two subtypes to mediate the same physiological function. This report raises several interesting questions for future research. For example, what adrenoceptor subtype mediates hepatic function in the α1A/α1B double KO mouse (O'Connell et al., 2003), which has no obvious metabolic defects? Can one of the other α1 subtypes mediate aortic vasoconstriction in α1D KO mice?