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The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells

Yingying, Ye LU ; Barghouth, Mohammad LU ; Luan, Cheng LU ; Kazim, Abdulla LU ; Zhou, Yuedan LU ; Eliasson, Lena LU ; Zhang, Enming LU ; Hansson, Ola LU ; Thevenin, Thomas LU and Renström, Erik LU (2020) In Molecular and Cellular Endocrinology 502. p.1-11
Abstract
The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion... (More)
The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1-silenced cells. Overexpression of α2δ-1 increased high-glucose/K+-stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2-silenced cells rescued the Tcf7l2-dependent impairment of Ca2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca2+-dependent insulin secretion. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
TCF7L2, α2δ-1, Type 2 Diabetes
in
Molecular and Cellular Endocrinology
volume
502
article number
110673
pages
1 - 11
publisher
Elsevier
external identifiers
  • scopus:85076248475
ISSN
0303-7207
DOI
10.1016/j.mce.2019.110673
language
English
LU publication?
yes
id
293bc097-7b63-4c4b-9775-77aa6fceb664
date added to LUP
2020-01-08 13:35:28
date last changed
2020-01-13 02:37:43
@article{293bc097-7b63-4c4b-9775-77aa6fceb664,
  abstract     = {The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1-silenced cells. Overexpression of α2δ-1 increased high-glucose/K+-stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2-silenced cells rescued the Tcf7l2-dependent impairment of Ca2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca2+-dependent insulin secretion.},
  author       = {Yingying, Ye and Barghouth, Mohammad and Luan, Cheng and Kazim, Abdulla and Zhou, Yuedan and Eliasson, Lena and Zhang, Enming and Hansson, Ola and Thevenin, Thomas and Renström, Erik},
  issn         = {0303-7207},
  language     = {eng},
  month        = {02},
  pages        = {1--11},
  publisher    = {Elsevier},
  series       = {Molecular and Cellular Endocrinology},
  title        = {The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells},
  url          = {http://dx.doi.org/10.1016/j.mce.2019.110673},
  doi          = {10.1016/j.mce.2019.110673},
  volume       = {502},
  year         = {2020},
}