Voltage-dependent ion channels in small-cell lung cancer cells.
Small-cell carcinoma of the lung is a highly lethal form of cancer associated with a wide variety of paraneoplastic syndromes. Using the patch-clamp technique, we have directly demonstrated the presence of voltage-gated K+, Na+, and Ca2+ channels in three cell lines of human small-cell carcinoma, NCI-H128, NCI-H69, and NCI-H146. Whole-cell currents were measured from the tumor cells held at -80 mV and depolarized to -60 to +120 mV. Outward K+ current (IK), which was found in every cell tested, reached 1.58 +/- 0.12 nA (mean +/- SE, n = 24 cells) for H128 cells and 2.14 +/- 0.18 nA (n = 41) for H69 cells in response to a test potential of +80 mV. Unlike H69 and H128 tumor cells, IK from H146 cells occasionally exhibited partial inactivation during the 60-ms pulse length and reached 0.94 +/- 0.15 nA (n = 18) in response to a +80 mV test potential. IK from each of the cell lines was significantly reduced by 4-aminopyridine and tetraethylammonium. The rapidly inactivating inward Na+ current (INa), recorded in H146 cells and about 30% of the H69 and H128 cells tested, demonstrated a peak amplitude of 58 +/- 6 pA (n = 11) at 0 mV and a reversal potential of 47 +/- 2 mV (n = 11). Externally applied tetrodotoxin quickly suppressed INa. For the H128 and H69 tumor cells, inward Ca2+ current (ICa), observed in about 25% of the cells exposed to 10 mM [Ca2+]o, peaked at 5.1 +/- 0.4 ms (n = 5) with an amplitude of 46 +/- 14 pA (n = 5) at +20 mV and partially inactivated over the 40-ms depolarization. In H128 cells exposed to isotonic Ba2+ (110 mM), inward currents with time courses similar to those of ICa were recorded. Nearly all H146 tumor cells demonstrated a significant inward Ca2+ current which peaked with an amplitude of 93 +/- 16 pA (n = 26) at +30 to +40 mV in the presence of 10 mM [Ca2+]o. Application of test potentials 2 s in duration revealed that H146 ICa inactivated in a voltage-dependent manner with a time constant on the order of seconds. Adjustment of the holding potential from -80 mV to -40 mV had no observable effect on the amplitude of the evoked current. These voltage-dependent ion channels may have integral roles in several small-cell carcinoma bioelectric phenomena, including secretion, resting membrane potential, and action potential generation.(ABSTRACT TRUNCATED AT 400 WORDS)
Pancrazio
J J
JJ
Department of Biomedical Engineering, University of Virginia Health Sciences Center, Charlottesville 22908.
Viglione
M P
MP
Tabbara
I A
IA
Kim
Y I
YI
D015220:Calcium Channels / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000503:physiopathology*; D002460:Cell Line; D004553:Electric Conductivity; D004594:Electrophysiology / Q000295:instrumentation / Q000379:methods; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D008175:Lung Neoplasms / Q000503:physiopathology*; D008564:Membrane Potentials; D015221:Potassium Channels / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000502:physiology*
D015220:Calcium Channels; D007473:Ion Channels; D015221:Potassium Channels; D015222:Sodium Channels