High constitutive activity of native H3 receptors regulates histamine neurons in brain

Some G-protein-coupled receptors display ‘constitutive activity’, that is, spontaneous activity in the absence of agonist1,2,3,4. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins3. The process has been shown to occur with recombinant receptors expressed at high density, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations5,6,7. Transgenic mice that express a constitutively active mutant of the β 2-adrenergic receptor display cardiac anomalies8; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases9,10. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor3,4. Here we show that two isoforms of the recombinant rat H3 receptor11,12 display high constitutive activity. Using drugs that abrogate this activity (‘inverse agonists’) and a drug that opposes both agonists and inverse agonists (‘neutral antagonist’), we show that constitutive activity of native H3 receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo . Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels.