Constitutive activity of the histamine H3 receptor

Constitutive activity has been mainly recorded for numerous overexpressed and/or mutated receptors. The histamine H3 receptor (H3R) is a target of choice to study the physiological relevance of this process. In rodent brain, postsynaptic H3Rs show high constitutive activity, and presynaptic H3 autoreceptors that show constitutive activity have a predominant role in inhibiting the activity of histamine neurons. H3R inverse agonists abrogate this constitutive brake and enhance histamine release in vivo. Some of these inverse agonists have entered clinical trials for the treatment of cognitive and food intake disorders. Studies performed in vitro and in vivo with proxyfan show that this H3R ligand is a ‘protean agonist’ – that is, a ligand with a spectrum of activity ranging from full agonism to full inverse agonism depending on the level of H3R constitutive activity. Consistent with its physiological and therapeutic relevance, the constitutive activity of H3R thus has a major function in the brain and regulates the activity of H3R-targeted drugs.