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Publication
Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls
pancreatic ß-cell insulin secretion.
Authors Dickerson MT, Dadi PK, Butterworth RB, Nakhe AY, Graff SM, Zaborska KE, Schaub
CM, Jacobson DA
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal The Journal of physiology
Year 2020
Date Published 11/1/2020
Volume : Pages 598 : 4887 - 4905
PubMed Reference 32790176
Abstract Tetraspanin (TSPAN) proteins regulate many biological processes, including
intracellular calcium (Ca2+ ) handling. TSPAN-7 is enriched in pancreatic islet
cells; however, the function of islet TSPAN-7 has not been identified. Here, we
characterize how ß-cell TSPAN-7 regulates Ca2+ handling and hormone secretion.
We find that TSPAN-7 reduces ß-cell glucose-stimulated Ca2+ entry, slows Ca2+
oscillation frequency and decreases glucose-stimulated insulin secretion.
TSPAN-7 controls ß-cell function through a direct interaction with L-type
voltage-dependent Ca2+ channels (CaV 1.2 and CaV 1.3), which reduces channel
Ca2+ conductance. TSPAN-7 slows activation of CaV 1.2 and accelerates recovery
from voltage-dependent inactivation; TSPAN-7 also slows CaV 1.3 inactivation
kinetics. These findings strongly implicate TSPAN-7 as a key regulator in
determining the set-point of glucose-stimulated Ca2+ influx and insulin
secretion., Glucose-stimulated insulin secretion (GSIS) is regulated by calcium
(Ca2+ ) entry into pancreatic ß-cells through voltage-dependent Ca2+ (CaV )
channels. Tetraspanin (TSPAN) transmembrane proteins control Ca2+ handling, and
thus they may also modulate GSIS. TSPAN-7 is the most abundant islet TSPAN and
immunostaining of mouse and human pancreatic slices shows that TSPAN-7 is highly
expressed in ß- and a-cells; however, the function of islet TSPAN-7 has not been
determined. Here, we show that TSPAN-7 knockdown (KD) increases
glucose-stimulated Ca2+ influx into mouse and human ß-cells. Additionally, mouse
ß-cell Ca2+ oscillation frequency was accelerated by TSPAN-7 KD. Because TSPAN-7
KD also enhanced Ca2+ entry when membrane potential was clamped with
depolarization, the effect of TSPAN-7 on CaV channel activity was examined.
TSPAN-7 KD enhanced L-type CaV currents in mouse and human ß-cells. Conversely,
heterologous expression of TSPAN-7 with CaV 1.2 and CaV 1.3 L-type CaV channels
decreased CaV currents and reduced Ca2+ influx through both channels. This was
presumably the result of a direct interaction of TSPAN-7 and L-type CaV channels
because TSPAN-7 coimmunoprecipitated with both CaV 1.2 and CaV 1.3 from primary
human ß-cells and from a heterologous expression system. Finally, TSPAN-7 KD in
human ß-cells increased basal (5.6 mM glucose) and stimulated (45 mM KCl + 14 mM
glucose) insulin secretion. These findings strongly suggest that TSPAN-7
modulation of ß-cell L-type CaV channels is a key determinant of ß-cell
glucose-stimulated Ca2+ entry and thus the set-point of GSIS.




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