It is generally accepted that the H2 receptor is positively coupled to the adenylyl cyclase system. The H2receptor activates adenylyl cyclase in membrane fractions in a guanyl nucleotide—sensitive manner (Johnson 1992). Direct evidence for the involvement a Gs-protein was shown by an enhanced GTP azidoanilide-labelling of Gs-like proteins in H2 receptor expressing Sf9 cells (Leopoldt etal. 1997). A large number of studies have shown that HA increases the levels of cAMP in brain, stomach, heart and adipose tissue in several species, including man (Hill et al. 1997; Schwartz etal. 1991).
In addition to elevation of cAMP levels via Gs-proteins, the H2 receptor may activate PLC via different G proteins. In differentiated HL-60 cells (Gespach et al. 1982; Seifert et al. 1992), parietal cells (Negulescu and Machen 1988), human keratinocytes (Koizumi and Ohkawara 1999), and HEPA, COS-7, and HEK-293 cells transfected with the canine H2 receptor (DelValle et al. 1992; Kühn et al. 1996; Wang et al. 1997), an H2-receptor mediated increase of the intracellular Ca2+ concentration was observed. HA was also found to increase the levels of InsP3 in various cell types (DelValle etal. 1992; Fitzsimons etal. 1999; Kühn et al. 1996; Legnazzi et al. 1998; Wang et al. 1996), and activation of both PKCa and PKCß has been observed (Wang et al. 1997). In COS-7 cells, co-expression of Gq/11-family members of G proteins, but not Gi or Gs, leads to a further H2-receptor mediated increase in InsP3 formation. Moreover, in guinea-pig membranes, HA stimulates via both H1- and H2-receptor incorporation of [a-32P]GTP azidoanilide into Gq/11-like proteins (Kühn etal. 1996).
In the nervous system, H2 receptors promote excitation by inhibition of a calcium-activated potassium conductance (Brown et al. 2001). This action is thought to occur through the cAMP-protein kinase A pathway. H2-mediated depolarizations in pyramidal cells and thalamus can also occur through cAMP modulation of cation channels (Brown et al. 2001). However, recent work has demonstrated that H2 receptor activation can paradoxically dampen high frequency firing by blocking Kv3.2, a voltage-gated potassium channel (Rudy and McBain 2001).
The H2 receptor is known to be rapidly desensitized in a homologous or heterolog-ous manner in a variety of cell lines (Holden et al. 1987; Sawutz et al. 1984; Schreurs et al. 1984; Smit et al. 1994). Several studies have pointed to phosphorylation of Ser/Thr residues in I3 by GRK2 and/or GRK3 in the process of homologous desensitization (Nakata et al. 1996; Rodriguez-Pena et al. 2000; Shayo et al. 2001), whereas the induction of phosphodiesterase activity was often suggested to explain heterologous desensitization (Holden et al. 1987). The H2 receptor will internalize within 10-60 min of agonist exposure (Smit et al. 1995). Following exposure for a few hours, expression of the H2 receptor is downregulated via both cAMP-dependent and cAMP-independent mechanisms (Smit et al. 1996b).
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