G protein-coupled receptor deorphanizations

Abstract

G protein-coupled receptors (GPCRs) are major regulators of intercellular interactions. They initiate these actions by being activated by a wide variety of natural ligands. Historically, ligands were discovered first, but the advent of molecular biology reversed this trend. Most GPCRs are identified on the basis of their DNA sequences and thus are initially unmatched to known natural ligands. They are termed orphan GPCRs. Discovering their ligands-i.e., "deorphanizing" the GPCRs-gave birth to the field of reverse pharmacology. This review discusses the present status of GPCR deorphanization, presents a few examples of successes and surprises, and highlights difficulties encountered in these efforts.

Figure 1

Evolution of the pharmacological specificity concept. Abbreviations: GHS, growth hormone secretagogue; GPCR, G protein–coupled receptor; OFQ/N, orphanin FQ or nociceptin; NOP, OFQ/N receptor; NPS, neuropeptide S.

Figure 2

(a) The G protein–coupled receptors (GPCRs) classified according to the GRAFS system (named on the basis of its five main classes: Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin). The numbers indicate the approximate numbers of receptors in the different classes. The ligands of the Glutamate and Secretin receptors are also indicated. (b) Schematic representation of the phylogenetic relationships of the human Rhodopsin GPCRs. The phylogenetic relationships are based on those discussed in Reference . Orphan GPCRs are shown in red. Some GPCR subgroups, analyzed as separate groups in Reference , have been placed according to their phylogenetic positions as described in Reference . Encircled areas outline phylogenetic clusters. Receptors with ambiguous relationships to other members are indicated by a dotted line.

Figure 2

(a) The G protein–coupled receptors (GPCRs) classified according to the GRAFS system (named on the basis of its five main classes: Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin). The numbers indicate the approximate numbers of receptors in the different classes. The ligands of the Glutamate and Secretin receptors are also indicated. (b) Schematic representation of the phylogenetic relationships of the human Rhodopsin GPCRs. The phylogenetic relationships are based on those discussed in Reference . Orphan GPCRs are shown in red. Some GPCR subgroups, analyzed as separate groups in Reference , have been placed according to their phylogenetic positions as described in Reference . Encircled areas outline phylogenetic clusters. Receptors with ambiguous relationships to other members are indicated by a dotted line.