{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,26]],"date-time":"2025-10-26T14:38:26Z","timestamp":1761489506714},"reference-count":0,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[1995,10,15]],"date-time":"1995-10-15T00:00:00Z","timestamp":813715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[1995,10,15]]},"abstract":"<jats:p>1. Human small\u2010cell lung cancer (SCLC) cells are believed to express the antigens responsible for the production of pathological antibodies in the Lambert\u2010Eaton syndrome (LES), a Ca2+ channel disorder in which quantal transmitter release from the motor nerve terminal is impaired. Whole\u2010cell patch\u2010clamp techniques were used to study the voltage\u2010dependent 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\u2010cell Ca2+ currents (ICa) in SCLC cells are sensitive to the dihydropyridine (DHP) nicardipine, omega\u2010conotoxin GVIA (omega\u2010CgTX GVIA) and omega\u2010agatoxin IVA (omega\u2010AgTX IVA). Nicardipine at 100 nM and 10 microM reduced ICa by 35 and 45% (n = 38 cells), respectively, while omega\u2010CgTX GVIA (1 microM) inhibited ICa by 32% (n = 31). Application of omega\u2010AgTX 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+)\u2010dependent 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\u2010AgTX IVA (100 nM). In contrast, omega\u2010CgTX GVIA (1 microM) was not as effective in altering increases in Cm. 4. From negative (\u201080 mV) and depolarized (\u201040 mV) holding potentials, both peak and plateau ICa were inhibited by the presence of LES antibodies (1 mg ml\u20101 IgG). LES serum also reduced depolarization\u2010induced 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\u2010CgTX GVIA (1 microM) or omega\u2010AgTX 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\u2010AgTX IVA was 38\u201084% 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\u2010CgTX GVIA was seen to be more effective. These results suggest that LES IgG downregulates P\u2010type Ca2+ channels and, possibly, to a lesser extent L\u2010type channels. 6. In view of recent evidence that P\u2010type Ca2+ channels mediate cholinergic transmitter release at the mammalian neuromuscular junction (NMJ), the expression of P\u2010type Ca2+ channels in the SCLC cells and the reactivity of LES IgG with these channels support the hypothesis that P\u2010type 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.<\/jats:p>","DOI":"10.1113\/jphysiol.1995.sp020968","type":"journal-article","created":{"date-parts":[[2014,12,17]],"date-time":"2014-12-17T09:50:52Z","timestamp":1418809852000},"page":"303-317","source":"Crossref","is-referenced-by-count":31,"title":["Inhibition of calcium currents and exocytosis by Lambert\u2010Eaton syndrome antibodies in human lung cancer cells."],"prefix":"10.1113","volume":"488","author":[{"given":"M P","family":"Viglione","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T J","family":"O'Shaughnessy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y I","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[1995,10,15]]},"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.1995.sp020968","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.1995.sp020968","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T03:12:25Z","timestamp":1698289945000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.1995.sp020968"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,10,15]]},"references-count":0,"journal-issue":{"issue":"2","published-print":{"date-parts":[[1995,10,15]]}},"alternative-id":["10.1113\/jphysiol.1995.sp020968"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.1995.sp020968","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,10,15]]}}}