Hunting for the function of orphan GPCRs - beyond the search for the endogenous ligand

Abstract

Seven transmembrane-spanning proteins (7TM), also called GPCRs, are among the most versatile and evolutionary successful protein families. Out of the 400 non-odourant members identified in the human genome, approximately 100 remain orphans that have not been matched with an endogenous ligand. Apart from the classical deorphanization strategies, several alternative strategies provided recent new insights into the function of these proteins, which hold promise for high therapeutic potential. These alternative strategies consist of the phenotypical characterization of organisms silenced or overexpressing orphan 7TM proteins, the search for constitutive receptor activity and formation of protein complexes including 7TM proteins as well as the development of synthetic, surrogate ligands. Taken together, a variety of ligand-independent functions can be attributed to orphan 7TM proteins that range from constitutive activity to complex formation with other proteins and include 'true' orphans for which no ligand exist and 'conditional' orphans that behave like orphans in the absence of ligand and as non-orphans in the presence of ligand.

Figure 1

Functions of orphan 7TM proteins. Orphan 7TM proteins can have various cellular functions. (A) They can depend on a yet-to-be identified natural ligand(s). (B) Orphan 7TM proteins can also display constitutive activity, mainly based on constitutive coupling to G-proteins and engaging different downstream signalling pathways. (C) This constitutive activity can be maintained by the presence of intramolecular N-terminal tethered ligands. (D) Medicinal chemistry allows the design and synthesis of suitable surrogate ligands that can modulate the activity of 7TM proteins. Orphan 7TM proteins can also exert their function in complex with other proteins (E–F) with different cellular localizations as extracellular (not shown, example GPR56 and TG 2), transmembrane or intracellular proteins and modulate their function or enzymatic activity. Heteromer formation with other GPCRs is a specific complex-dependent action of orphan 7TM proteins that occurs between different cellular GPCRs and are found in different species as for heteromers between viral orphan 7TM proteins and host cell GPCRs. Additionally, deorphanized GPCRs can behave in distinct cellular contexts as conditional orphans and allosterically modulate the function of their binding partner in the absence of their natural ligands.