In the field of GPCRs it is currently well accepted that receptors can induce signal transduction without the presence of the agonist. The notion of constitutive receptor activity has also resulted in the introduction of the class of inverse agonists, ligands able to reduce agonist-independent signalling. Recently, all human HA receptors have been shown to have constitutive activity (Alewijnse et al. 1998; Bakker et al. 2000; Morisset et al. 2000; Morse et al. 2001; Wieland et al. 2001). Overexpression of the H1 receptor results in an agonist-independent production of InsP3 and NF-kB activation (Bakker et al. 2000, 2001), which can be inhibited by H1 antagonists. Among these are well-known therapeutics, such as cetirizine (Zyrtec®), loratadine (Claritin®), and epinastine (Flurinol®). Similarly, all well-known therapeutics acting at the H2 receptor (e.g. cimetidine, Tagamet®, rantidine, Zantac®) can act as inverse agonists at constitutively active H2 receptors, thereby reducing basal cellular cAMP levels in transfected cell lines (Alewijnse et al. 1998; Smit et al. 1996a). Also, the Gi/o coupled H3 and H4 receptor show constitutive activity in transfec-ted cells as determined by modulation of cAMP levels (Morisset et al. 2000; Wieland et al. 2001), arachidonic acid release or [35S]GTPyS binding (Morisset et al. 2000; Morse et al. 2001). Interestingly, the H3 receptor is one of the few examples of a G protein coupled receptor showing a high level of constitutive activity in a physiological system (Morisset et al. 2000; Wieland et al. 2001). These findings strongly suggest that constitutively active H3 receptors are relevant for the regulation of histaminergic (and possibly other) neuronal activity.
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