Evidence for an interaction between proinsulin C-peptide and GPR146

J Endocrinol. 2013 Jul 11;218(2):B1-8. doi: 10.1530/JOE-13-0203. Print 2013.

Abstract

Microvascular diseases, such as retinopathies, neuropathies, and nephropathies, are a devastating consequence of type 1 and type 2 diabetes. The etiology of diabetes-associated microvascular dysfunction is poorly understood, and, likewise, treatment modalities for these disorders are limited. Interestingly, proinsulin C-peptide has been shown to play a protective role against diabetes-associated complications in experimental animals and in diabetic humans and is thus an attractive therapeutic target. However, an important step in the development of C-peptide-based therapeutics is identification of the C-peptide receptor, which is likely a G protein-coupled receptor (GPCR). Using a unique Deductive Ligand-Receptor Matching Strategy, we sought to determine whether one of the known orphan GPCRs is essential for C-peptide signaling. Knockdown of GPR146, but not GPR107 or GPR160, blocked C-peptide-induced cFos expression in KATOIII cells. Furthermore, stimulation with C-peptide caused internalization of GPR146, and examples of punctate colocalization were observed between C-peptide and GPR146 on KATOIII cell membranes. These data indicate that GPR146 is likely a part of the C-peptide signaling complex and provide a platform for the elucidation of the C-peptide signalosome.

Keywords: C-peptide; GPR146; insulin receptor; orphan GPCR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • C-Peptide / metabolism*
  • C-Peptide / pharmacology
  • Cell Line
  • Humans
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptor, Insulin / metabolism
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • C-Peptide
  • GPR146 protein, human
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptor, Insulin