Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice.
Insulin is secreted from pancreatic beta cells in response to an elevation of cytoplasmic Ca(2+) resulting from enhanced Ca(2+) influx through voltage-gated Ca(2+) channels. Mouse beta cells express several types of Ca(2+) channel (L-, R- and possibly P/Q-type). beta cell-selective ablation of the gene encoding the L-type Ca(2+) channel subtype Ca(v)1.2 (betaCa(v)1.2(-/-) mouse) decreased the whole-cell Ca(2+) current by only approximately 45%, but almost abolished first-phase insulin secretion and resulted in systemic glucose intolerance. These effects did not correlate with any major effects on intracellular Ca(2+) handling and glucose-induced electrical activity. However, high-resolution capacitance measurements of exocytosis in single beta cells revealed that the loss of first-phase insulin secretion in the betaCa(v)1.2(-/-) mouse was associated with the disappearance of a rapid component of exocytosis reflecting fusion of secretory granules physically attached to the Ca(v)1.2 channel. Thus, the conduit of Ca(2+) entry determines the ability of the cation to elicit secretion.
Schulla
Verena
V
Institut für Pharmakologie und Toxikologie, TU München, Biedersteiner Strasse 29, D-80802 München, Germany.
Renström
Erik
E
Feil
Robert
R
Feil
Susanne
S
Franklin
Isobel
I
Gjinovci
Asllan
A
Jing
Xing-Jun
XJ
Laux
Dirk
D
Lundquist
Ingmar
I
Magnuson
Mark A
MA
Obermüller
Stefanie
S
Olofsson
Charlotta S
CS
Salehi
Albert
A
Wendt
Anna
A
Klugbauer
Norbert
N
Wollheim
Claes B
CB
Rorsman
Patrik
P
Hofmann
Franz
F
D000818:Animals; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D005089:Exocytosis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D051379:Mice
D020746:Calcium Channels, L-Type; D017931:DNA Primers; D007328:Insulin; C419385:L-type calcium channel alpha(1C)