Although the H3 receptor was first suggested to exist in 1983, detailed information on this receptor's transduction mechanisms was only obtained recently. Until the cloning of the receptor cDNA in 1999 (Lovenberg et al. 1999), the most convincing evidence had been obtained by Clark and Hill (1996). In rat brain membranes, a PTX-sensitive stimulation of [35S]GTPyS binding was observed. In agreement with these observations, a PTX-sensitive inhibition of cAMP accumulation in response to H3 agonists has been observed in a variety of transfected cells expressing the human or rat H3 receptor (Drutel et al. 2001; Lovenberg et al. 1999; Morisset et al. 2000). Prior to the H3 cloning, inhibitory effects of PTX were known on H3 signalling (Clark and Hill 1996; Endou et al. 1994; Nozaki and Spere-lakis 1989; Oike et al. 1992; Poli et al. 1993; Takeshita et al. 1998), and these had already supported the involvement of a Gi/o-protein in the H3-receptor mediated responses, but the modulation of cAMP levels in brain tissue had not been previously observed (Garbarg et al. 1989). Recently, it was reported that the H3-mediated regulation of histidine decarboxylase activity can be controlled via the cAMP-adenylate cyclase-PKA pathway, but direct modulation of brain cAMP levels were not investigated (Gomez-Ramirez et al. 2002). In transfected cell lines, the H3 receptor has also been reported to activate [35S]GTPyS binding (Morisset et al. 2000), arachidonic acid release (Morisset et al. 2000), the MAPK pathway (Drutel et al. 2001), the Na+ /H+ exchanger (Silver et al. 2001) and to inhibit Ca2+ influx and exocytosis of [3H]noradrenaline from transfected SH-SY5Y-H3 cells (Silver et al. 2002).
Although the mechanisms of H3 receptor signalling in physiological systems are not clear, it is known that H3 activation leads to inhibition of transmitter release. The list of transmitters modulated by H3 receptors includes not only HA (the basis for the autoreceptor function), but many others: glutamate, norepinephrine, dopamine, acetylcholine, serotonin, and several peptides (Brown etal. 2001; Hough 1999). An inhibition of high threshold Ca2+ currents has been shown to mediate some of these effects. Activation of inwardly-rectifying potassium channels, another mechanism commonly used by PTX-sensitive autoreceptors, has not been demonstrated for the H3 receptor (Brown et al. 2001).
With respect to the regulation of H3-receptor responses, no detailed information is currently available. In the guinea-pig intestine, H3-receptor responses are desensitized rapidly (Perez-Garcia et al. 1998), but the actual biochemical mechanisms have so far not been investigated.
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