Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146.
G protein-coupled receptors (GPCRs) are the most abundant receptor family encoded by the human genome and are the targets of a high percentage of drugs currently in use or in clinical trials for the treatment of diseases such as diabetes and its associated complications. Thus, orphan GPCRs, for which the ligand is unknown, represent an important untapped source of therapeutic potential for the treatment of many diseases. We have identified the previously orphan GPCR, GPR146, as the putative receptor of proinsulin C-peptide, which may prove to be an effective treatment for diabetes-associated complications. For example, we have found a potential role of C-peptide and GPR146 in regulating the function of the retinal pigment epithelium, a monolayer of cells in the retina that serves as part of the blood-retinal barrier and is disrupted in diabetic macular oedema. However, C-peptide signalling in this cell type appears to depend at least in part on extracellular glucose concentration and its interaction with insulin. In this review, we discuss the therapeutic potential of orphan GPCRs with a special focus on C-peptide and GPR146, including past and current strategies used to 'deorphanize' this diverse family of receptors, past successes and the inherent difficulties of this process.
Department of Pathology, St Louis University School of Medicine, St Louis, MO, USA.
G R
GR
Kolar
Department of Pharmacology and Physiology, St Louis University School of Medicine, St Louis, MO, USA.
S M
SM
Grote
Department of Pharmacology and Physiology, St Louis University School of Medicine, St Louis, MO, USA.
G L C
GL
Yosten
D000818:Animals; D002096:C-Peptide / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation; D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D002096:C-Peptide; C583411:GPR146 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D005947:Glucose
C-peptide; G protein-coupled receptor; GPR146; diabetes; diabetes-associated complications; orphan GPCR