The autoimmune response in the Lambert-Eaton myasthenic syndrome (LES), is thought to be triggered by the presence of a tumor, particularly small-cell lung cancer (SCLC). Presynaptic calcium channels at the neuromuscular junction (NMJ) are the target of the antibodies in I?S patients, thus it is reasonable to assume that the putative autoantigens in SCLC cells possess the same molecular characteristics as the P/O-type Ca2+ channels found at the human NMJ. The current proposal is aimed at verifying a central hypothesis: SCLc cells express omega-agatoxin WA-sensitive P/Q-type voltage-dependent Ca2+ channels (VDCCs), which act as the primary immunogen in this disease; these channels initiate and maintain LBS patient's autoimmune response and the autoantibodies so produced then destructively cross-react with the target antigens at the NMJ. The long term objective of this proposal is two-fold: 1) to identify the primary and secondary autoantigens that initiate and maintain the production of pathogenic antibodies in L?S; and 2) to determine their pathogenic role in clinical manifestation of the peripheral motor and autonomic nervous system dysfunctions characterizing this disease. This study will pursue four Specific Aims: [1] To determine the specificity of L?S autoantibodies for subtypes of VDCCs; [2] To determine the cross-reactivity of LBS IgG using cloned alpha1 Ca2+ channel subunit currents expressed in stably transfected human embryonic kidney (HBK293) cell lines and Xenopus oocytes; [3] To develop and characterize an experimental autoimmune animal model of the Lambert-Baton syndrome (EALES); and [4] To determine P/Q-type Ca2+ channel vs. synaptotagmin dysfunction at the NMJs of mice with passively transferred LES.
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