TY - JOUR
T1 - The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells
AU - Ye, Yingying
AU - Barghouth, Mohammad
AU - Luan, Cheng
AU - Kazim, Abdulla
AU - Zhou, Yuedan
AU - Eliasson, Lena
AU - Zhang, Enming
AU - Hansson, Ola
AU - Thevenin, Thomas
AU - Renström, Erik
N1 - Publisher Copyright:
© 2019
PY - 2020/2/15
Y1 - 2020/2/15
N2 - 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.
AB - 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.
KW - Tcf7l2
KW - Type 2 diabetes
KW - α2δ-1
UR - http://www.scopus.com/inward/record.url?scp=85076248475&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076248475&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2019.110673
DO - 10.1016/j.mce.2019.110673
M3 - Article
C2 - 31805307
AN - SCOPUS:85076248475
SN - 0303-7207
VL - 502
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
M1 - 110673
ER -