ISSN:
1432-1424
Schlagwort(e):
Small-cell lung cancer cells
;
Voltagegated sodium channels
;
Action potentials
;
Lambert-Eaton syndrome
;
Paraneoplastic neurological disorders
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Biologie
,
Chemie und Pharmazie
Notizen:
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 μm 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.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1007/BF00234661
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