Voltage-dependent sodium channels in human small-cell lung cancer cells: Role in action potentials and inhibition by lambert-eaton syndrome IgG |
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Authors: | J K W Blandino M P Viglione W A Bradley H K Oie Y I Kim |
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Institution: | (1) Department of Biomedical Engineering, University of Virginia School of Medicine, Box 377, 22908 Charlottesville, Virginia;(2) Department of Neuroscience, University of Virginia School of Medicine, 22908 Charlottesville, Virginia;(3) National Cancer Institute, Navy Medical Oncology Branch, Naval Hospital, 20892 Bethesda, Maryland;(4) Department of Neurology, University of Virginia School of Medicine, 22908 Charlottesville, Virginia |
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Abstract: | Sodium channels of human small-cell lung cancer (SCLC) cells were examined with whole-cell and single-channel patch clamp methods. In the tumor cells from SCLC cell line NCI-H146, the majority of the voltage-gated Na+ channels are only weakly tetrodotoxin (TTX)-sensitive (K
d
=215 mm). With the membrane potential maintained at –60 to –80 mV, these cells produced all-or-nothing action potentials in response to depolarizing current injection (>20 pA). Similar all-ornothing spikes were also observed with anodal break excitation. Removal of external Ca2+ did not affect the action potential production, whereas 5 m TTX or substitution of Na+ with choline abolished it. Action potentials elicited in the Ca2+-free condition were reversibly blocked by 4 mm MnCl2 due to the Mn2+-induced inhibition of voltage-dependent sodium currents (I
Na). Therefore, Na+ channels, not Ca2+ channels, underlie the excitability of SCLC cells. Whole-cell I
Na was maximal with step-depolarizing stimulations to 0 mV, and reversed at +45.2 mV, in accord with the predicted Nernst equilibrium potential for a Na+-selective channel. I
Na evoked by depolarizing test potentials (–60 to +40 mV) exhibited a transient time course and activation/ inactivation kinetics typical of neuronal excitable membranes; the plot of the Hodgkin-Huxley parameters, m and h, also revealed biophysical similarity between SCLC and neuronal Na+ channels. The single channel current amplitude, as measured with the inside-out patch configuration, was 1.0 pA at –20 mV with a slope conductance of 12.1 pS. The autoantibodies implicated in the Lambert-Eaton myasthenic syndrome (LES), which are known to inhibit I
Ca and I
Na in bovine adrenal chromaffin cells, also significantly inhibited I
Na in SCLC cells. These results indicate that (i) action potentials in human SCLC cells result from the regenerative increase in voltage-gated Na+ channel conductance; (ii) fundamental characteristics of SCLC Na+ channels are the same as the classical sodium channels found in a variety of excitable cells; and (iii) in some LES patients, SCLC Na+ channels are an additional target of the pathological IgG present in the patients' sera.Department of Biomedical EngineeringThis study was supported by National Institutes of Health grant NS18607 and a research grant from the Muscular Dystrophy Association. Dr. Y.I. Kim is the recipient of a Javits Neuroscience Investigator Award from the National Institute of Neurological Disorder and Stroke. |
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Keywords: | Small-cell lung cancer cells Voltagegated sodium channels Action potentials Lambert-Eaton syndrome Paraneoplastic neurological disorders |
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