1. Human small-cell lung cancer (SCLC) cells are believed to express the 
antigens responsible for the production of pathological antibodies in the 
Lambert-Eaton syndrome (LES), a Ca2+ channel disorder in which quantal 
transmitter release from the motor nerve terminal is impaired. Whole-cell 
patch-clamp techniques were used to study the voltage-dependent Ca2+ channels 
expressed by H146 SCLC cells and the effects of LES antibodies on these 
channels. The types of Ca2+ channels were determined using biophysical 
properties and pharmacological sensitivity to several antagonists. 2. Whole-cell 
Ca2+ currents (ICa) in SCLC cells are sensitive to the dihydropyridine (DHP) 
nicardipine, omega-conotoxin GVIA (omega-CgTX GVIA) and omega-agatoxin IVA 
(omega-AgTX IVA). Nicardipine at 100 nM and 10 microM reduced ICa by 35 and 45% 
(n = 38 cells), respectively, while omega-CgTX GVIA (1 microM) inhibited ICa by 
32% (n = 31). Application of omega-AgTX IVA at 50 and 100 nM to the cancer cells 
decreased ICa by 41 and 42%, respectively (n = 22). 3. Measurement of cell 
membrane capacitance (Cm) revealed that Ca(2+)-dependent exocytosis underlies 
the secretory activity of SCLC cells. Exocytosis, when induced by step 
depolarizing pulses and measured by increases in Cm, was markedly inhibited by 
nicardipine (10 microM) and omega-AgTX IVA (100 nM). In contrast, omega-CgTX 
GVIA (1 microM) was not as effective in altering increases in Cm. 4. From 
negative (-80 mV) and depolarized (-40 mV) holding potentials, both peak and 
plateau ICa were inhibited by the presence of LES antibodies (1 mg ml-1 IgG). 
LES serum also reduced depolarization-induced increases in Cm by 48% (n = 15). 
5. To determine whether the LES antibodies are downregulating a specific type(s) 
of Ca2+ channel, nicardipine (10 microM), omega-CgTX GVIA (1 microM) or 
omega-AgTX IVA (100 nM) was applied to tumour cells that had been previously 
exposed to LES serum for 24 h. The most pronounced change was that omega-AgTX 
IVA was 38-84% less effective at reducing ICa after the IgG treatment. The 
effectiveness of nicardipine was diminished by 18% after incubation with the LES 
antibodies, whereas the omega-CgTX GVIA was seen to be more effective. These 
results suggest that LES IgG downregulates P-type Ca2+ channels and, possibly, 
to a lesser extent L-type channels. 6. In view of recent evidence that P-type 
Ca2+ channels mediate cholinergic transmitter release at the mammalian 
neuromuscular junction (NMJ), the expression of P-type Ca2+ channels in the SCLC 
cells and the reactivity of LES IgG with these channels support the hypothesis 
that P-type Ca2+ channels in these cancer cells may trigger the autoantibody 
production in this disorder. The antibodies so produced are implicated in the 
functional impairment of the Ca2+ channels characteristic of LES.