Voltage-dependent Ion Channels in Small-Cell Lung Cancer

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 k4. Na4, and (a24 channels in three cell lines of human small-cell carcinoma, NCI-HI28, NCI-H69, and NCI-HI46. Whole-cell currents were measured from the tumor cells held at —¿ 80 mV and depolarized to -60 to +120 mV. Outward K* current (/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, /Kfrom H146 cells occasionally exhibited partial ¡nactivationduring the 60-ms pulse length and reached 0.94 ±0.15 nA (n = 18) in response to a +80 mV test potential. 7Kfrom each of the cell lines was significantly reduced by 4-aminopyridine and tetraethylammonium. The rapidly inac tivating inward Na* current (/%,), 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 /N>. For the H128 and H69 tumor cells, inward C;r* current (/,.), observed in about 25% of the cells exposed to 10 HIM|(V+|„. 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-ins depolarization. In H128 cells exposed to isotonic Ba24 (110 HIM), inward currents with time courses similar to those of /c. were recorded. Nearly all H146 tumor cells demonstrated a significant inward ( u24current which peaked with an amplitude of 93 ± 16 pA (n = 26) at +30 to +40 mV in the presence of 10 HIM[Ca2+]„. Application of test potentials 2 s in duration revealed that H146 /( „¿ 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. Further more, a current hypothesis concerning the autoimmune etiology of Lam bert-Eaton syndrome suggests that small-cell carcinoma tumor cells possess (a24 channels which may serve as the antigenic stimulus for the production of these autoantibodies. Our finding is consistent with this hypothesis.