NEGATIVE ANTAGONISTS PROMOTE AN INACTIVE CONFORMATION OF THE BETA(2)-ADRENERGIC RECEPTOR

The beta2-adrenergic receptor undergoes isomerization between an inact ive conformation (R) and an active conformation (R). The formation of the active conformation of the receptor molecule can be promoted by a drenergic agonists or by mutations in the third cytoplasmic domain tha t constitutively activate the receptor. Here we show that, of several beta-adrenergic receptor-blocking drugs tested, only two, ICI 118551 a nd betaxolol, inhibit the basal signaling activity of the beta2-adrene rgic receptor, thus acting as negative antagonists. We document the mo lecular properties of the more efficacious ICI 118551; (i) it shows hi gher affinity for the inactive form of the receptor and (ii) it inhibi ts the spontaneous formation of a beta-adrenergic receptor kinase subs trate by the receptor. These properties are opposite those of adrenerg ic agonists, indicating that, in a fashion reciprocal to that of agoni sts, negative antagonists promote the formation of an inactive conform ation of the receptor.