A new HA receptor on chromosome 18 was rapidly identified by various groups by the use of the sequence information on the H3 receptor (Liu etal. 2001a; Morse etal. 2001; Nakamura et al. 2000; Nguyen et al. 2001; Oda et al. 2000; Zhu et al. 2001). Within the transmembrane domains, the new H4 receptor shows approximately 60 per cent homology with the H3 receptor, whereas little overall sequence homology with the other HA receptors can be noticed (Fig. 17.1). The high homology with the H3 receptor also explains the overlapping pharmacology; many H3 agonists and antagonists also act on the H4 receptor, although differences have been observed. The human H4 receptor gene exhibits an exon/intron arrangement identical to the H3 receptor gene (Oda et al. 2000). In view of the discovery of multiple H3-receptor isoforms, H4 isoforms may be identified soon. No actual data on the ligand binding site are currently available, but a remarkable species specificity has been reported (Liu et al. 2001b). The amino acid sequences of rat, mouse, guinea-pig and human H4 receptors are overall 65-70 per cent homologous and show substantial differences in their pharmacological profile; the affinity of [3H]-HA varies considerably, from 4 nM (human) to 136nM (rat) (Liu etal. 2001b).
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