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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
|August 28, 2013
PubMed

Insights

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

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Biology

Background:

  • Diabetic microvascular complications like retinopathy, neuropathy, and nephropathy significantly impact patient health.
  • The precise mechanisms driving diabetes-associated microvascular dysfunction remain unclear, limiting effective treatment options.
  • Proinsulin C-peptide exhibits protective effects against diabetes complications, making it a promising 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.
  • To establish a foundation for developing C-peptide-based therapies.

Main Methods:

  • Employed a Deductive Ligand-Receptor Matching Strategy to screen orphan GPCRs.
  • Utilized gene knockdown techniques to assess the necessity of specific GPCRs (GPR146, GPR107, GPR160) for C-peptide signaling.
  • Investigated C-peptide-induced cellular responses, including cFos expression and receptor internalization in KATOIII cells.

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 of 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 critical platform for further elucidation of the C-peptide signalosome.
  • This research paves the way for understanding C-peptide's therapeutic potential in diabetic complications.

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