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Evidence for an interaction between proinsulin C-peptide and GPR146

Gina L C Yosten1, Grant R Kolar, Lauren J Redlinger

  • 1Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 S Grand Boulevard, Saint Louis, Missouri 63104, USA. gyosten@slu.edu

The Journal of Endocrinology
|June 14, 2013
PubMed

Insights

Researchers identified G protein-coupled receptor 146 (GPR146) as a key component in C-peptide signaling. This discovery advances understanding of C-peptide

Area of Science:

  • Endocrinology and Metabolism
  • Molecular Cell Biology
  • Diabetology

Background:

  • Diabetic microvascular complications like retinopathy, neuropathy, and nephropathy are significant health issues.
  • The precise mechanisms underlying diabetes-associated microvascular dysfunction remain unclear, limiting therapeutic options.
  • Proinsulin C-peptide exhibits protective effects against diabetes complications, making it a potential therapeutic target.

Purpose of the Study:

  • To identify the G protein-coupled receptor (GPCR) responsible for C-peptide signaling.
  • To investigate the role of orphan GPCRs in mediating C-peptide's biological effects.

Main Methods:

  • Employed a Deductive Ligand-Receptor Matching Strategy to screen orphan GPCRs.
  • Utilized siRNA-mediated knockdown of candidate GPCRs (GPR146, GPR107, GPR160) in KATOIII cells.
  • Assessed C-peptide-induced cFos expression as a readout for signaling pathway activation.
  • Investigated GPR146 localization and interaction with C-peptide using cell membrane studies and colocalization assays.

Main Results:

  • Knockdown of GPR146, but not GPR107 or GPR160, abrogated C-peptide-induced cFos expression.
  • C-peptide stimulation led to the internalization of GPR146.
  • Observed punctate colocalization between C-peptide and GPR146 on KATOIII cell membranes, suggesting a direct interaction.

Conclusions:

  • GPR146 is identified as a likely component of the C-peptide signaling complex.
  • These findings provide a foundation for further research into the C-peptide signalosome and its therapeutic potential.
  • This study opens new avenues for developing C-peptide-based therapies for diabetic complications.
Keywords:
C-peptideGPR146insulin receptororphan GPCR

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