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

Abstract

Some G-protein-coupled receptors display 'constitutive activity', that is, spontaneous activity in the absence of agonist. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins. 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 concentrations. Transgenic mice that express a constitutively active mutant of the beta2-adrenergic receptor display cardiac anomalies; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor. Here we show that two isoforms of the recombinant rat H3 receptor 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.

Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway

“…Firstly, the finding that H 3 R are positively coupled to the MAPK cascade in COS-7 cells [9], and secondly, that H 3 R activation results in PLA 2 activation [24]. Given that H 3 R are G i -coupled [12;21], and that the βγ i subunit is responsible for the activation of MAPK by G i -coupled receptors [25], we assumed that H 3 R would activate MAPK via βγ i .…”

Synthesis and Structure−Activity Relationships of Conformationally Constrained Histamine H3 Receptor Agonists

“…49,50 Currently, the H 3 receptor is one of the few examples of GPCRs for which constitutive activity has been reported to appear in vivo (rat and mouse brain). The occurrence of constitutive activity leads to a reclassification of H 3 antagonists into inverse agonists (i.e.…”

Role of H3-Receptor-Mediated Signaling in Anxiety and Cognition in Wild-Type and Apoe–/– Mice

“…They are highly expressed throughout the brain (Arrang et al, 1998;Lovenberg et al, 2000;Drutel et al, 2001) on presynaptic terminals of histaminergic and nonhistaminergic neurons and also modulate the release of other neurotransmitters (Schlicker et al, 1988(Schlicker et al, , 1989(Schlicker et al, , 1993Fink et al, 1990;Clapham and Kilpatrick, 1992). As H 3 receptors display high constitutive activity, previously known antagonists were reclassified as inverse agonists (Morisset et al, 2000;Wieland et al, 2001).…”