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Voltage-dependent Ion Channels in Small-Cell Lung Cancer Cells¹

Departments of Biomedical Engineering [J. J. P., Y. I. K.], Neurology [M. P. V., Y. I. K.], and Internal Medicine [I. A. T.], University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

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 (I_K), 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, I_K 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. I_K from each of the cell lines was significantly reduced by 4-aminopyridine and tetraethylammonium. The rapidly inactivating inward Na⁺ current (I_Na), 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 I_Na. For the H128 and H69 tumor cells, inward Ca²⁺ current (I_Ca), 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 I_Ca 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 I_Ca 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. Furthermore, a current hypothesis concerning the autoimmune etiology of Lambert-Eaton syndrome suggests that small-cell carcinoma tumor cells possess Ca²⁺ channels which may serve as the antigenic stimulus for the production of these autoantibodies. Our finding is consistent with this hypothesis.

¹ This investigation was supported by NIH Grant NS18607 and a research grant from the Muscular Dystrophy Association. Y. I. K. is the recipient of a Jacob Javits Neuroscience Investigator Award from NINDS.

² To whom requests for reprints should be addressed, at Department of Biomedical Engineering, Box 377, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

Received 3/28/89. Revised 7/25/89. Accepted 8/ 7/89.

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