hich is much lower than that of YL529. The seven transmembrane domain GPCRs constitute the largest membrane receptor family. These CSP-1103 custom synthesis proteins respond to a wide variety of extracellular molecules and play a crucial role in cell-to-cell communication by transmitting extracellular signals into cells. Based on sequence homology, different receptor subfamilies have been defined: rhodopsin, secretin, adhesion, glutamate, frizzled receptors and other 7TM proteins. In contrast to the latter group, all others are considered to be G-protein coupled. The involvement of GPCRs in a variety of physiological and pathophysiological processes makes this class of proteins the most common target of pharmaceutical drugs. Genome sequencing projects indicated that approximately 400 sequences belong to the nonodourant GPCR family in the human genome. Most of them have been matched with known ligands using different strategies. However, in spite of the extensive and long-standing efforts of academic and industrial research to pair 7TM proteins to potential ligands, 91 non-odourant receptors still remain orphans and another 37 are awaiting further input to be considered as deorphanized, according to IUPHAR. Deorphanization needs, as a minimal requirement, that two or more refereed papers from independent research groups should demonstrate activity of the ligand at the receptor, with a potency that is consistent with a physiological function. In some cases, although two independent groups have reported a pairing, others have failed to reproduce this finding and thus the deorphanization process requires further 
validation. Although deorphanization still remains an important step towards the identification of the function of orphan 7TM proteins, other alternative strategies have become equally important over the PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19809470 last years to provide new insights into the function of orphan 7TM proteins. Among these strategies are the phenotypical characterization of animal models with modified expression of 7TM proteins of interest, the characterization of constitutive receptor activity, the association of 7TM proteins with other proteins such as GPCRs, transporters or enzymes in heteromeric protein complexes and the identification of synthetic, surrogate ligands. The most recent advances in the identification of the function of 7TM proteins, using alternative strategies, will be the focus of this article. Pathophysiological functions of orphan 7TM proteins Because orphan 7TM proteins represent a potential resource for future drug development, various approaches, including transgenic and gene knockout approaches in mice, have been used to decipher their biological roles and their involvement in different pathophysiological conditions such as cancer, metabolism, neurodegenerative disorders and energy metabolism diseases. British Journal of Pharmacology 172 32123228 3213 BJP R Ahmad et al. Functions of orphan 7TM proteins. Orphan 7TM proteins can have various cellular functions. They can depend on a yet-to-be identified natural ligand. Orphan 7TM proteins can also display constitutive activity, mainly based on constitutive coupling to G-proteins and engaging different downstream signalling pathways. This constitutive activity can be maintained by the presence of intramolecular N-terminal tethered ligands. 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 i
