PMID- 32790176
OWN - NLM
STAT- MEDLINE
DCOM- 20210301
LR  - 20240402
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 598
IP  - 21
DP  - 2020 Nov
TI  - Tetraspanin-7 regulation of L-type voltage-dependent calcium channels controls 
      pancreatic beta-cell insulin secretion.
PG  - 4887-4905
LID - 10.1113/JP279941 [doi]
AB  - KEY POINTS: Tetraspanin (TSPAN) proteins regulate many biological processes, 
      including intracellular calcium (Ca(2+) ) handling. TSPAN-7 is enriched in 
      pancreatic islet cells; however, the function of islet TSPAN-7 has not been 
      identified. Here, we characterize how beta-cell TSPAN-7 regulates Ca(2+) handling 
      and hormone secretion. We find that TSPAN-7 reduces beta-cell glucose-stimulated 
      Ca(2+) entry, slows Ca(2+) oscillation frequency and decreases glucose-stimulated 
      insulin secretion. TSPAN-7 controls beta-cell function through a direct interaction 
      with L-type voltage-dependent Ca(2+) channels (Ca(V) 1.2 and Ca(V) 1.3), which 
      reduces channel Ca(2+) conductance. TSPAN-7 slows activation of Ca(V) 1.2 and 
      accelerates recovery from voltage-dependent inactivation; TSPAN-7 also slows 
      Ca(V) 1.3 inactivation kinetics. These findings strongly implicate TSPAN-7 as a 
      key regulator in determining the set-point of glucose-stimulated Ca(2+) influx 
      and insulin secretion. ABSTRACT: Glucose-stimulated insulin secretion (GSIS) is 
      regulated by calcium (Ca(2+) ) entry into pancreatic beta-cells through 
      voltage-dependent Ca(2+) (Ca(V) ) channels. Tetraspanin (TSPAN) transmembrane 
      proteins control Ca(2+) 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 beta- and alpha-cells; however, the 
      function of islet TSPAN-7 has not been determined. Here, we show that TSPAN-7 
      knockdown (KD) increases glucose-stimulated Ca(2+) influx into mouse and human 
      beta-cells. Additionally, mouse beta-cell Ca(2+) oscillation frequency was accelerated 
      by TSPAN-7 KD. Because TSPAN-7 KD also enhanced Ca(2+) entry when membrane 
      potential was clamped with depolarization, the effect of TSPAN-7 on Ca(V) channel 
      activity was examined. TSPAN-7 KD enhanced L-type Ca(V) currents in mouse and 
      human beta-cells. Conversely, heterologous expression of TSPAN-7 with Ca(V) 1.2 and 
      Ca(V) 1.3 L-type Ca(V) channels decreased Ca(V) currents and reduced Ca(2+) 
      influx through both channels. This was presumably the result of a direct 
      interaction of TSPAN-7 and L-type Ca(V) channels because TSPAN-7 
      coimmunoprecipitated with both Ca(V) 1.2 and Ca(V) 1.3 from primary human beta-cells 
      and from a heterologous expression system. Finally, TSPAN-7 KD in human beta-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 
      beta-cell L-type Ca(V) channels is a key determinant of beta-cell glucose-stimulated 
      Ca(2+) entry and thus the set-point of GSIS.
CI  - (c) 2020 The Authors. The Journal of Physiology (c) 2020 The Physiological Society.
FAU - Dickerson, Matthew T
AU  - Dickerson MT
AUID- ORCID: 0000-0002-6187-3951
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Dadi, Prasanna K
AU  - Dadi PK
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Butterworth, Regan B
AU  - Butterworth RB
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Nakhe, Arya Y
AU  - Nakhe AY
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Graff, Sarah M
AU  - Graff SM
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Zaborska, Karolina E
AU  - Zaborska KE
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Schaub, Charles M
AU  - Schaub CM
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
FAU - Jacobson, David A
AU  - Jacobson DA
AUID- ORCID: 0000-0003-1816-5375
AD  - Department of Molecular Physiology and Biophysics, Vanderbilt University, 7425B 
      MRB IV, Nashville, TN, USA.
LA  - eng
GR  - R01 DK097392/DK/NIDDK NIH HHS/United States
GR  - P60 DK020593/DK/NIDDK NIH HHS/United States
GR  - DK-097392/NH/NIH HHS/United States
GR  - R01 DK115620/DK/NIDDK NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - U24 DK098085/DK/NIDDK NIH HHS/United States
GR  - T32 DK101003/DK/NIDDK NIH HHS/United States
GR  - P30 EY008126/EY/NEI NIH HHS/United States
GR  - P30 DK020593/DK/NIDDK NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - T32 DK007563/DK/NIDDK NIH HHS/United States
GR  - U54 EY032442/EY/NEI NIH HHS/United States
GR  - U24 DK059637/DK/NIDDK NIH HHS/United States
GR  - DK-115620/NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200901
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Calcium Channels, L-Type)
RN  - 0 (Insulin)
RN  - IY9XDZ35W2 (Glucose)
RN  - SY7Q814VUP (Calcium)
SB  - IM
CIN - J Physiol. 2021 Mar;599(6):1733-1734. PMID: 33347614
MH  - Animals
MH  - Calcium/metabolism
MH  - Calcium Channels, L-Type/genetics/metabolism
MH  - *Glucagon-Secreting Cells/metabolism
MH  - Glucose/metabolism
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - *Insulin-Secreting Cells/metabolism
MH  - Mice
PMC - PMC8095317
MID - NIHMS1649451
OTO - NOTNLM
OT  - calcium handling
OT  - insulin secretion
OT  - pancreatic beta-cell
OT  - tetraspanin-7
OT  - voltage-dependent calcium channel
EDAT- 2020/08/14 06:00
MHDA- 2021/03/02 06:00
PMCR- 2021/11/01
CRDT- 2020/08/14 06:00
PHST- 2020/04/20 00:00 [received]
PHST- 2020/07/20 00:00 [accepted]
PHST- 2020/08/14 06:00 [pubmed]
PHST- 2021/03/02 06:00 [medline]
PHST- 2020/08/14 06:00 [entrez]
PHST- 2021/11/01 00:00 [pmc-release]
AID - 10.1113/JP279941 [doi]
PST - ppublish
SO  - J Physiol. 2020 Nov;598(21):4887-4905. doi: 10.1113/JP279941. Epub 2020 Sep 1.