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Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma
Israa Mohammad Al-Amily1, Marie Sjögren1, Pontus Duner2
1Department of Clinical Science, SUS, Division of Islet Cell Physiology, University of Lund, SE-205 02 Malmö, Sweden.
Abstract:
The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation to the mitochondrial outer membrane voltage-dependent anion Channel-1 (VDAC1) expression in pancreatic β-cells. GPR56KD attenuated the Coll III-induced suppression of P70S6K, JNK, AKT, NFκB, STAT3, and STAT5 phosphorylation/activity in INS-1 cells cultured at 20 mM glucose (glucotoxicity) for 72 h. GPR56-KD also increased Chrebp, Txnip, and Vdac1 while decreasing Vdac2 mRNA expression. In GPR56-KD islet β-cells, Vdac1 was co-localized with SNAP-25, demonstrating its plasma membrane translocation. This resulted in ATP loss, reduced cAMP production and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 and human EndoC βH1 cells. The latter defects were reversed by an acute inhibition of VDAC1 with an antibody or the VDAC1 inhibitor VBIT-4. We demonstrate that Coll III potentiates GSIS by increasing cAMP and preserving β-cell functionality under glucotoxic conditions in a GPR56-dependent manner by attenuating the inflammatory response. These results emphasize GPR56 and VDAC1 as drug targets in conditions with impaired β-cell function.
Insights
Collagen Type III activates G Protein-Coupled Receptor 56 (GPR56) to support pancreatic beta-cell function. GPR56 and VDAC1 are potential drug targets for improving beta-cell function in disease.
Area of Science:
- Endocrinology and Metabolism
- Cell Biology
- Molecular Signaling
Background:
- G Protein-Coupled Receptor 56 (GPR56/ADGRG1) activation by Collagen Type III (Coll III) influences cell growth and survival.
- Pancreatic beta-cells are crucial for insulin secretion and are susceptible to glucotoxicity.
- The interplay between GPR56, Collagen III, and mitochondrial function in beta-cells is not fully understood.
Purpose of the Study:
- To investigate the signaling pathways linking GPR56 activation by Coll III to mitochondrial VDAC1 expression in pancreatic beta-cells.
- To elucidate the role of GPR56 and VDAC1 in regulating beta-cell function, insulin secretion, and survival under glucotoxic conditions.
Main Methods:
- Utilized INS-1 and human EndoC βH1 cells under high glucose conditions (glucotoxicity).
- Employed GPR56 knockdown (GPR56KD) to assess its impact on signaling cascades and gene expression.
- Investigated VDAC1 localization, ATP levels, cAMP production, and glucose-stimulated insulin secretion (GSIS).
- Tested the effects of VDAC1 inhibition using an antibody and VBIT-4.
Main Results:
- GPR56KD attenuated Coll III-induced signaling pathways (P70S6K, JNK, AKT, NFκB, STAT3/5) under glucotoxicity.
- GPR56KD increased VDAC1 expression and promoted its translocation to the plasma membrane, leading to ATP loss.
- Impaired GSIS and reduced cAMP production were observed in GPR56KD cells, which were reversed by VDAC1 inhibition.
- Coll III enhanced GSIS by increasing cAMP and preserving beta-cell function via GPR56, attenuating inflammation.
Conclusions:
- Collagen Type III potentiates glucose-stimulated insulin secretion through GPR56 by preserving beta-cell function under glucotoxic stress.
- GPR56 signaling is critical for maintaining beta-cell ATP levels and cAMP production, partly through regulating VDAC1 expression and localization.
- GPR56 and VDAC1 represent promising therapeutic targets for treating conditions characterized by impaired beta-cell function.
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