Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome.
The aim of this study was to clarify whether autoimmunity against P/Q-type voltage-gated calcium channels (VGCCs) in the cerebellum was associated with the pathogenesis of paraneoplastic cerebellar degeneration (PCD) with Lambert-Eaton myasthenic syndrome (LEMS). We used human autopsy cerebellar tissues from three PCD-LEMS patients and six other disease patients including one with LEMS as the controls. We compared cerebellar P/Q-type VGCC in these patients and controls for the amount and ratio of autoantibody-channel complex using an 125I-omega-conotoxin MVIIC-binding assay with Scatchard analysis, and their distribution using autoradiography. The quantity of cerebellar P/Q-type VGCC measured by Scatchard analysis were reduced in PCD-LEMS patients (63.0 +/- 7.0 fmol/mg, n = 3), compared with the controls (297.8 +/- 38.9 fmol/mg, n = 6). The ratio of autoantibody-VGCC complexes to total P/Q-type VGCCs measured by immunoprecipitation assay were increased in PCD-LEMS patients. We analysed cerebellar specimens by autoradiography using (125)I-omega-conotoxin MVIIC, which specifically binds to P/Q-type VGCCs. In PCD-LEMS cerebellum, the toxin binding sites of P/Q-type VGCCs were markedly reduced compared with controls, especially in the molecular layer, which is the richest area of P/Q-type VGCCs in the normal cerebellum. This suggests that P/Q-type VGCCs of the cerebellar molecular layer is the immunological target in developing PCD-LEMS.
Fukuda
Taku
T
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Motomura
Masakatsu
M
Nakao
Yoko
Y
Shiraishi
Hirokazu
H
Yoshimura
Toshiro
T
Iwanaga
Keisuke
K
Tsujihata
Mitsuhiro
M
Eguchi
Katsumi
K
D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D001345:Autoradiography; D020864:Calcium Channels, N-Type / Q000276:immunology* / Q000378:metabolism*; D002524:Cerebellar Ataxia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004546:Elapid Venoms / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020362:Paraneoplastic Cerebellar Degeneration / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020960:omega-Conotoxins / Q000378:metabolism / Q000494:pharmacology
D001323:Autoantibodies; D020864:Calcium Channels, N-Type; D004546:Elapid Venoms; D007457:Iodine Radioisotopes; D020960:omega-Conotoxins; C020273:dendrotoxin