SELECTIVE-INHIBITION OF ADENYLYL-CYCLASE BY OCTOPAMINE VIA A HUMAN CLONED ALPHA(2A)-ADRENOCEPTOR

1 In this study we have compared the abilities of the enantiomers of t he structural isomers of the phenolamines, octopamine and synephrine, and the catecholamines, noradrenaline and adrenaline, to couple select ively a human cloned alpha(2A)-adrenoceptor, stably expressed in a Chi nese hamster ovary (CHO) cell line, to G-protein linked second messeng er pathways mediating an increase and a decrease in cyclic AMP product ion. 2 The catecholamines couple the alpha(2A)-adrenoceptor to both an increase and a decrease in the rate of cyclic AMP production. In the absence of pertussis toxin pretreatment both catecholamines tested sho wed a dose-dependent decrease with a maximum at 100 nM. After pertussi s toxin pretreatment they both produced a dose-dependent increase in c yclic AMP production with a maximum at 10 mu M. 3 The phenolamines, oc topamine and synephrine were only able to couple the alpha(2A)-adrenoc eptor to a dose-dependent decrease in cyclic AMP production at concent rations up to 1 mM, with the synephrine isomers being more potent than the corresponding octopamine isomers. The meta-isomers of both phenol amines were more potent than the corresponding para-isomers and the (- )-enantiomers were more potent than the (+)-enantiomers. Thus, (-)-met a-synephrine [(-)-phenylephrine] was the most effective isomer tested with an observable decrease occurring between 100 nM and 1 mu M. 4 The effects of octopamine and the catecholamines on the decrease in cycli c AMP production were additive at submaximal concentrations, whilst oc topamine reduced the stimulant effect of submaximal concentrations of noradrenaline on cyclic AMP production after pertussis toxin pretreatm ent. 5 The time courses of the inhibitory effects of both meta-octopam ine and noradrenaline were parallel and peaked after a 1 min exposure to the agonist. In contrast, the stimulant effects of noradrenaline af ter pertussis toxin pretreatment were of a much slower time course wit h a maximum effect occurring after a 5 min incubation period. 6 Since octopamine and synephrine occur naturally in, and are co-released with catecholamines from, mammalian tissues, the results of the present st udy suggest that the human cloned alpha(2A)-adrenoceptor can be couple d selectively by different endogenous agonists to G-protein pathways m ediating the regulation of adenylyl cyclase activity.