Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis.
An oscillatory increase in pancreatic beta cell cytoplasmic free Ca2+ concentration, [Ca2+]i, is a key feature in glucose-induced insulin release. The role of the voltage-gated Ca2+ channel beta3 subunit in the molecular regulation of these [Ca2+]i oscillations has now been clarified by using beta3 subunit-deficient beta cells. beta3 knockout mice showed a more efficient glucose homeostasis compared to wild-type mice due to increased glucose-stimulated insulin secretion. This resulted from an increased glucose-induced [Ca2+]i oscillation frequency in beta cells lacking the beta3 subunit, an effect accounted for by enhanced formation of inositol 1,4,5-trisphosphate (InsP3) and increased Ca2+ mobilization from intracellular stores. Hence, the beta3 subunit negatively modulated InsP3-induced Ca2+ release, which is not paralleled by any effect on the voltage-gated L type Ca2+ channel. Since the increase in insulin release was manifested only at high glucose concentrations, blocking the beta3 subunit in the beta cell may constitute the basis for a novel diabetes therapy.
The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, S-17176 Stockholm, Sweden. per-olof.berggren@molmed.ki.se
Per-Olof
PO
Berggren
Shao-Nian
SN
Yang
Manabu
M
Murakami
Alexander M
AM
Efanov
Sabine
S
Uhles
Martin
M
Köhler
Tilo
T
Moede
Andreas
A
Fernström
Ioulia B
IB
Appelskog
Craig A
CA
Aspinwall
Sergei V
SV
Zaitsev
Olof
O
Larsson
Lina Moitoso
LM
de Vargas
Claudia
C
Fecher-Trost
Petra
P
Weissgerber
Andreas
A
Ludwig
Barbara
B
Leibiger
Lisa
L
Juntti-Berggren
Christopher J
CJ
Barker
Jesper
J
Gromada
Marc
M
Freichel
Ingo B
IB
Leibiger
Veit
V
Flockerzi
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D015220:Calcium Channels; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D021122:Protein Subunits; D018160:Receptors, Cytoplasmic and Nuclear; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D005947:Glucose; D002118:Calcium