Article ; Online: Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane.
2023 Volume 13, Issue 3
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 ... ...
| 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. |
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| MeSH term(s) | Humans ; Adenosine Triphosphate/metabolism ; Cell Membrane/metabolism ; Collagen Type III/metabolism ; Glucose/pharmacology ; Glucose/metabolism ; Islets of Langerhans/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Voltage-Dependent Anion Channel 1/genetics ; Voltage-Dependent Anion Channel 1/metabolism |
| Chemical Substances | Adenosine Triphosphate (8L70Q75FXE) ; Collagen Type III ; Glucose (IY9XDZ35W2) ; Receptors, G-Protein-Coupled ; VDAC1 protein, human ; Voltage-Dependent Anion Channel 1 (EC 1.6.-) ; ADGRG1 protein, human |
| Language | English |
| Publishing date | 2023-03-18 |
| Publishing country | Switzerland |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2701262-1 |
| ISSN | 2218-273X ; 2218-273X |
| ISSN (online) | 2218-273X |
| ISSN | 2218-273X |
| DOI | 10.3390/biom13030557 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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