Blockers of the delayed-rectifier potassium current in pancreatic beta-cells enhance glucose-dependent insulin secretion.
Delayed-rectifier K+ currents (I(DR)) in pancreatic beta-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K+ channel, K(V)2.1, is expressed in beta-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I(DR) in rodent beta-cells. A novel peptidyl inhibitor of K(V)2.1/K(V)2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration approximately 1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to beta-cell physiology. In mouse beta-cells, GxTX-1 inhibits 90% of I(DR) and, as for K(V)2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the beta-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the beta-cell I(DR), which may provide advantages over currently used therapies for the treatment of type 2 diabetes.
Herrington
James
J
Department of Ion Channels, Merck Research Laboratories, RY80N-C31, P.O. Box 2000, Rahway, NJ 07065-0900, USA. james_herrington@merck.com
Zhou
Yun-Ping
YP
Bugianesi
Randal M
RM
Dulski
Paula M
PM
Feng
Yue
Y
Warren
Vivien A
VA
Smith
McHardy M
MM
Kohler
Martin G
MG
Garsky
Victor M
VM
Sanchez
Manuel
M
Wagner
Michael
M
Raphaelli
Kristin
K
Banerjee
Priya
P
Ahaghotu
Chinweze
C
Wunderler
Denise
D
Priest
Birgit T
BT
Mehl
John T
JT
Garcia
Maria L
ML
McManus
Owen B
OB
Kaczorowski
Gregory J
GJ
Slaughter
Robert S
RS
D000595:Amino Acid Sequence; D000818:Animals; D051668:Delayed Rectifier Potassium Channels / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D013111:Spider Venoms / Q000737:chemistry / Q000494:pharmacology
D051668:Delayed Rectifier Potassium Channels; D007328:Insulin; D010455:Peptides; D026902:Potassium Channel Blockers; D013111:Spider Venoms; C096469:hanatoxin; D005947:Glucose