For many years the molecular characteristics of the targets for HA remained unknown. Until the early nineteen nineties, the classification of the HA receptors was based solely on pharmacological findings. Although biochemical data suggested that HA receptors were G protein-coupled receptors (GPCRs) (e.g. signal transduction pathways, GTP-shifts of agonist binding), unequivocal proof of this was not provided for any HA receptor until 1991. Now, four different HA receptor subtypes (all GPCRs) have been identified. Except for the H3 and H4 receptor, the homology between the various HA receptors is very low (Fig. 17.1), even in the seven transmembrane domains. Nevertheless, all four of these receptor proteins contain a negatively charged aspartate residue in transmembrane (TM) 3, which is considered to be the anchor point for the protonated amine function of HA. The receptor proteins all contain the various conserved amino acids of the rhodopsin-like family (e.g. Asp in TM2, 2 conserved Cys residues forming a disulphide bridge, Asp-Arg-Tyr/Phe at the end of TM3, Asn-Pro-X-X-Tyr motif at the end of TM6), including an eighth alpha helical structure in the C-terminal tail. In this section, we will review the present biochemical and molecular biological data on the characteristics of the HA receptors.
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