High constitutive activity of native H-3 receptors regulates histamine neurons in brain

Some G-protein-coupled receptors display 'constitutive activity', that is, spontaneous activity in the absence of agonist(1-4). This means that a prop ortion of the receptor population spontaneously undergoes an allosteric tra nsition, leading to a conformation that can bind G proteins(3). The process has been shown to occur with recombinant receptors expressed at high densi ty, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations(5-7). Transgenic mice that express a constitu tively active mutant of the beta (2)-adrenergic receptor display cardiac an omalies(8); and spontaneous receptor mutations leading to constitutive acti vity are at the origin of some human diseases(9,10). Nevertheless, this pro cess has not previously been found to occur in animals expressing normal le vels of receptor(3,4). Here we show that two isoforms of the recombinant ra t H-3 receptor(11,12) display high constitutive activity. Using drugs that abrogate this activity ('inverse agonists') and a drug that opposes both ag onists and inverse agonists ('neutral antagonist'), we show that constituti ve activity of native H-3 receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo. Inverse agonists may theref ore rnd therapeutic applications, even in the case of diseases involving no n-mutated receptors expressed at normal levels.