Rhodopsin Subfamilies Bind Different Classes of Ligand

Interestingly, the concordance of phylogenies (Figure 10.2) and the 7TMR classification into four classes according to ligand size (Figure 10.1) produces a biologically relevant interpretation for the designations of a, p, g and 5: a for aminergic ligands, p for brain-gut peptides, g ligands for their Gi preference, and 5 ligands because they are the most diverse.

Thus, the a family of rhodopsin receptors interacts predominantly with ami-nergic-like ligands, typified by monoamine neurotransmitters, and it seems entirely appropriate to model their pharmacology on rhodopsin and to extrapolate from its three-dimensional (3D) structure. The p subfamily can be remembered for its homogeneous contingent of brain-gut peptides. The g subfamily is dominated by ligands important for immune cell attraction or responses, and while it is tempting to make an association with that other important group of immune proteins, the g-globulins, the most consistent GPCR feature for all members of this subfamily is their preference for Gi proteins. The 5 subfamily is undoubtedly the most diverse in terms of ligand preference, ranging from the sublime olfactory stimuli provided by exotic small molecules to the ridiculous clustering of an extremely diverse ligand set, covering purine specificity to protease cleavage of a tethered ligand, together with cysteinyl-leukotrienes and the largest, most heterogeneous hormones, the glycoprotein cystine-knot growth factors, a subset that also includes the insulinlike relaxin molecule.

Demarcation of the receptor groups according to ligand size determines that the a, p, g, and 5 designations conform to the increasing molecular weights of the respective ligands. It is remarkable that the GRAFS classification of phylogenetic relationships supports the ligand-based classification of the rhodopsin receptor family shown in Figure 10.1, reinforcing the many clues that support biologically meaningful, functional, and evolutionary relationships. This could be the nearest that 7TMR analyses have approached to the ultimate goal of functional genomics.

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