A comparison of agonist-specific coupling of cloned human alpha(2)-adrenoceptor subtypes

1 The agonist-specific coupling properties of the three cloned human alpha (2)-adrenoceptor subtypes have been compared, when expressed at similar lev els in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (+/- )-meta-octopamine as agonists. 2 Noradrenaline can couple the receptor to both the inhibition and stimulat ion of forskolin-stimulated cyclic AMP production in all three receptor sub types, with the relative strength of the coupling to the pathways varying f or each of the receptor subtypes. 3 meta-Octopamine selectively couples the alpha (2A)-adrenoceptor only to t he inhibition of forskolin-stimulated cyclic AMP production. However, meta- octopamine couples the alpha (2B)- and alpha (2C)-adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. 4 The relative potency of meta-octopamine to noradrenaline varies between t he different alpha (2)-adrenoceptor subtypes. The effects of meta-octopamin e are around two orders of magnitude less potent than those of noradrenalin e on both the alpha (2A)- and alpha (2B)-adrenoceptor subtypes. In contrast , in the case of the alpha (2C)-adrenoceptor, meta-octopamine is only one o rder of magnitude less potent than noradrenaline in the stimulation of fors kolin-stimulated cyclic AMP production and, in addition, is equipotent with noradrenaline in the inhibition of forskolin-stimulated cyclic AMP product ion and has an increased maximal response. This raises the possibility that ,meta-octopamine may have physiologically important actions via alpha (2C)- adrenoceptors in vivo. 5 The results show that the modulation of cyclic AMP production occurs in b oth a subtype- and agonist-specific manner for alpha (2A)-adrenoceptors and in a subtype specific manner for alpha (2B)- and alpha (2C)-adrenoceptors.