The calcium channel subunit gamma-4 is regulated by MafA and necessary for pancreatic beta-cell specification
(2019) In Communications Biology 2.- Abstract
- Voltage-gated Ca2+ (CaV) channels trigger glucose-induced insulin secretion in pancreatic beta-cell and their dysfunction increases diabetes risk. These heteromeric complexes include the main subunit alpha1, and the accessory ones, including subunit gamma that remains unexplored. Here, we demonstrate that CaV gamma subunit 4 (CaVγ4) is downregulated in islets from human donors with diabetes, diabetic Goto-Kakizaki (GK) rats, as well as under conditions of gluco-/lipotoxic stress. Reduction of CaVγ4 expression results in decreased expression of L-type CaV1.2 and CaV1.3, thereby suppressing voltage-gated Ca2+ entry and glucose stimulated insulin exocytosis. The most important finding is that CaVγ4 expression is controlled by the... (More)
- Voltage-gated Ca2+ (CaV) channels trigger glucose-induced insulin secretion in pancreatic beta-cell and their dysfunction increases diabetes risk. These heteromeric complexes include the main subunit alpha1, and the accessory ones, including subunit gamma that remains unexplored. Here, we demonstrate that CaV gamma subunit 4 (CaVγ4) is downregulated in islets from human donors with diabetes, diabetic Goto-Kakizaki (GK) rats, as well as under conditions of gluco-/lipotoxic stress. Reduction of CaVγ4 expression results in decreased expression of L-type CaV1.2 and CaV1.3, thereby suppressing voltage-gated Ca2+ entry and glucose stimulated insulin exocytosis. The most important finding is that CaVγ4 expression is controlled by the transcription factor responsible for beta-cell specification, MafA, as verified by chromatin immunoprecipitation and experiments in beta-cell specific MafA knockout mice (MafAΔβcell). Taken together, these findings suggest that CaVγ4 is necessary for maintaining a functional differentiated beta-cell phenotype. Treatment aiming at restoring CaVγ4 may help to restore beta-cell function in diabetes. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/36ff3d24-6aed-491e-b1f6-e43d3d7b4081
- author
- Luan, Cheng LU ; Yingying, Ye LU ; Singh, Tania LU ; Barghouth, Mohammad LU ; Eliasson, Lena LU ; Artner, Isabella LU ; Zhang, Enming LU and Renström, Erik LU
- organization
-
- Diabetes - Islet Patophysiology (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Endocrine Cell Differentiation and Function (research group)
- Stem Cell Center
- Department of Clinical Sciences, Malmö
- Diabetes - Islet Cell Exocytosis (research group)
- Faculty of Medicine
- publishing date
- 2019-03-15
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Communications Biology
- volume
- 2
- article number
- 106
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:30911681
- scopus:85071018959
- pmid:30911681
- ISSN
- 2399-3642
- DOI
- 10.1038/s42003-019-0351-4
- language
- English
- LU publication?
- yes
- id
- 36ff3d24-6aed-491e-b1f6-e43d3d7b4081
- date added to LUP
- 2019-04-21 23:33:50
- date last changed
- 2024-02-14 21:50:45
@article{36ff3d24-6aed-491e-b1f6-e43d3d7b4081, abstract = {{Voltage-gated Ca2+ (CaV) channels trigger glucose-induced insulin secretion in pancreatic beta-cell and their dysfunction increases diabetes risk. These heteromeric complexes include the main subunit alpha1, and the accessory ones, including subunit gamma that remains unexplored. Here, we demonstrate that CaV gamma subunit 4 (CaVγ4) is downregulated in islets from human donors with diabetes, diabetic Goto-Kakizaki (GK) rats, as well as under conditions of gluco-/lipotoxic stress. Reduction of CaVγ4 expression results in decreased expression of L-type CaV1.2 and CaV1.3, thereby suppressing voltage-gated Ca2+ entry and glucose stimulated insulin exocytosis. The most important finding is that CaVγ4 expression is controlled by the transcription factor responsible for beta-cell specification, MafA, as verified by chromatin immunoprecipitation and experiments in beta-cell specific MafA knockout mice (MafAΔβcell). Taken together, these findings suggest that CaVγ4 is necessary for maintaining a functional differentiated beta-cell phenotype. Treatment aiming at restoring CaVγ4 may help to restore beta-cell function in diabetes.}}, author = {{Luan, Cheng and Yingying, Ye and Singh, Tania and Barghouth, Mohammad and Eliasson, Lena and Artner, Isabella and Zhang, Enming and Renström, Erik}}, issn = {{2399-3642}}, language = {{eng}}, month = {{03}}, publisher = {{Nature Publishing Group}}, series = {{Communications Biology}}, title = {{The calcium channel subunit gamma-4 is regulated by MafA and necessary for pancreatic beta-cell specification}}, url = {{http://dx.doi.org/10.1038/s42003-019-0351-4}}, doi = {{10.1038/s42003-019-0351-4}}, volume = {{2}}, year = {{2019}}, }