The H1 receptor belongs to the family of Ca2+—mobilizing GPCRs. Activation of this receptor leads to the hydrolysis of phosphatidyl 4,5-biphosphate (PI(4,5)P2) resulting in the formation of the second messengers inositol (1,4,5) trisphosphate (InsP3) and 1,2-diacylglycerol (DAG). HA induces the production of inositol phosphates in many tissues including airway smooth muscle, intestinal smooth muscle, vascular smooth muscle, and heart (Barnes 1991; Claro et al. 1989; Donaldson and Hill 1986; Orellana et al. 1987; Sakuma et al. 1988). In guinea-pig brain, the magnitude of this response correlates well with the density of H1 receptors (Carswel! and Young 1986; Daum etal. 1983). Studies with bacterial toxins, Ga-subunit antibodies and [a-32P]GTP azidoanilide incoporation into Ga-subunits have shown that the stimulation of phospholipase C (PLC) occurs via Gaq/11 proteins (Gutowski etal. 1991; Kuhn etal. 1996; Leopoldt etal. 1997; Orellana etal. 1987).
The main physiological consequence of the production of inositol phosphates is the elevation of intracellular Ca2+, characterized by a rapid transient rise of the intracellular Ca2+
concentration, which is followed by a sustained elevation of the Ca2+ concentration. Experiments in Ca2+—free medium suggest that the sustained response is highly dependent on the influx of extracellular calcium, whereas the transient increase is caused by the release of Ca2+ from intracellular Ca2+ stores (Leurs etal. 1994b). The generated InsP3 is responsible for the rapid, transient release component; InsP3 receptors in the endoplasmic reticulum bind InsP3 and release Ca2+ into the cytosol. Recent evidence suggests that the formation of DAG is probably involved in the Ca2+ influx. DAG activates protein kinase C (PKC) and protein kinase D. Activated PKC has many cellular functions, including desensitization of the H1 receptor via receptor phosphorylation (Fujimoto et al. 1999; Smit et al. 1992) and transcriptional downregulation of H1-receptor expression (Pype etal. 1998). Moreover, the H1 receptor—mediated production of DAG has been shown to stimulate Ca2+ influx by activating transient receptor potential (TRP) channels (homologs of Drosophila TRP proteins (Hofmann etal. 1999)), which are thought to mediate capacitative Ca2+ entry (Birnbaumer etal. 1996).
Since Ca2+ and PKC are involved in the regulation of many cellular functions, the stimulation of PLC activity can explain a wide variety of secondary signalling events after stimulation of the H1 receptor. These include the Ca2+/calmodulin-dependent activation of the nitric oxide synthetase/guanylate cyclase pathway (Casale etal. 1985; Duncan etal. 1980; Hattori et al. 1988; Leurs et al. 1991a; Schmidt et al. 1990; Sertl et al. 1987; Yuan et al. 1993), the release of arachidonic acid via phoshoplipase A2 activation along with the subsequent generation of arachidonic acid metabolites such as prostacyclin and thromboxane A2 (Baenziger etal. 1980; Leurs etal. 1994b; Resink etal. 1987), the modulation of cAMP via crosstalk with other receptors (e.g. H2-, adenosine A2-, and vasoactive intestinal polypeptide receptors (Al-Gadi and Hill 1987; Donaldson et al. 1989; Magistretti and Schorderet 1985; Marley et al. 1991; Palacios et al. 1978)) and the activation of the transcription factors (e.g. nuclear factor of activated T cells [NF-AT] (Boss et al. 1998) and nuclear factor kappa B [NF-kB]) (Aoki et al. 1998; Bakker et al. 2001; Hu et al. 1999).
Besides the activation of second messenger pathways via the Gaq/11 subunits, several H1 receptor responses are mediated via other G protein signalling modules. In specific cell types the H1 receptor has been shown to activate pertussis toxin (PTX)—sensitive G;/o proteins linked to the elevation of intracellular [Ca2+] (Seifert et al. 1994a), to the modulation of a non-selective cation current (Wang and Kotlikoff 2000) or to the activation of phospholipase A2 (Leurs et al. 1994b; Murayama et al. 1990). Moreover, activation of phospholipase D by the H1 receptor is secondary to the activation of PLC (Natarajan and Garcia 1993). However, in 1321N1 astrocytoma cells, part of the HA-stimulated phospholipase D activity occurs in the absence of PKC activation (Dawson etal. 1993; Natarajan and Garcia 1993) and has been suggested to be mediated via the small G protein ARF (Mitchell et al. 1998).
In the nervous system, H1 receptor stimulation nearly always leads to depolarization and/or an increase in firing frequency (Brown et al. 2001). Stimulatory mechanisms which have been identified include blockade of a leak potassium conductance, activation of a calcium-independent, tetrodotoxin-insensitive sodium current, enhancement of NMDA currents, and activation of other cation channels. H1-mediated hyperpolarizations also occur (Brown etal. 2001).
H1 -receptor responsiveness is well regulated by desensitization, internalization, and down-regulation. H1 -receptor desensitization can be both homologous and heterologous; the latter is often the result of excessive PKC activation (Leurs et al. 1991b; Smit et al. 1992; Zamani etal. 1995). Recent studies of Fukui and coworkers showed PKC-mediated phosphorylation of Ser396 and, especially, Ser398; seem involved in the PKC-induced desensitization (Fujimoto et al. 1999). In bovine airway smooth muscle cells PKC-mediated blunting of HA-induced contractions was accompanied by a transcriptional downregulation of H1 -receptor mRNA (Pype et al. 1998). Young and coworkers were able to show H1-receptor internalization upon short-term HA exposure of U373 MG astrocytoma cells (Hishinuma and Young 1995), whereas in transfected CHO cells a PKC-independent H1-receptor downregulation was observed (Smit et al. 1996c). Detailed information on the molecular aspects of these processes is not presently available.
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