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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
Summary
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.
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