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The calcium channel subunit gamma-4 is regulated by MafA and necessary for pancreatic beta-cell specification

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 (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)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Communications Biology
volume
2
article number
106
publisher
Nature Research
external identifiers
  • pmid:30911681
  • scopus:85071018959
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
2019-09-26 04:32:59
@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 Research},
  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},
}