Biophysical and pharmacological properties of the voltage-gated potassium current of human pancreatic beta-cells.
Voltage-gated potassium (Kv) currents of human pancreatic islet cells were studied by whole-cell patch clamp recording. On average, 75% of the cells tested were identified as beta-cells by single cell, post-recording RT-PCR for insulin mRNA. In most cells, the dominant Kv current was a delayed rectifier. The delayed rectifier activated at potentials above -20 mV and had a V(1/2) for activation of -5.3 mV. Onset of inactivation was slow for a major component (tau = 3.2 s at +20 mV) observed in all cells; a smaller component (tau = 0.30 s) with an amplitude of approximately 25% was seen in some cells. Recovery from inactivation had a tau of 2.5 s at -80 mV and steady-state inactivation had a V(1/2) of -39 mV. In 12% of cells (21/182) a low-threshold, transient Kv current (A-current) was present. The A-current activated at membrane potentials above -40 mV, inactivated with a time constant of 18.5 ms at -20 mV, and had a V(1/2) for steady-state inactivation of -52 mV. TEA inhibited total Kv current with an IC50 = 0.54 mm and PAC, a disubstituted cyclohexyl Kv channel inhibitor, inhibited with an IC50 = 0.57 microm. The total Kv current was insensitive to margatoxin (100 nm), agitoxin-2 (50 nm), kaliotoxin (50 nm) and ShK (50 nm). Hanatoxin (100 nm) inhibited total Kv current by 65% at +20 mV. Taken together, these data provide evidence of at least two distinct types of Kv channels in human pancreatic beta-cells and suggest that more than one type of Kv channel may be involved in the regulation of glucose-dependent insulin secretion.
Herrington
James
J
Department of Ion Channels, Merck Research Laboratories, PO Box 2000, RY-80N-C31, Rahway, NJ 07065, USA. james_herrington@merck.com
Sanchez
Manuel
M
Wunderler
Denize
D
Yan
Lizhen
L
Bugianesi
Randal M
RM
Dick
Ivy E
IE
Clark
Sam A
SA
Brochu
Richard M
RM
Priest
Birgit T
BT
Kohler
Martin G
MG
McManus
Owen B
OB
D055592:Biophysical Phenomena; D001703:Biophysics; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D012604:Scorpion Venoms; D019789:Tetraethylammonium / Q000494:pharmacology*
C460479:4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)cyclohexanone; D003512:Cyclohexanones; D051668:Delayed Rectifier Potassium Channels; D009498:Neurotoxins; D010455:Peptides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; C096469:hanatoxin; C077910:margatoxin; D019789:Tetraethylammonium