Abstract

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(s)

Biological Sciences

Publication Status

Free Access

Comments

National Institutes of Health, Grant HL121456

Keywords and Phrases

C-peptide; diabetes; diabetes-associated complications; G protein-coupled receptor; GPR146; orphan GPCR

International Standard Serial Number (ISSN)

1365-2796; 0954-6820

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2025 Wiley, All rights reserved.

Publication Date

01 Jan 2017

PubMed ID

27306986

Download

Full Text Link

Included in

Biology Commons

Share

 
COinS