Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse.
Somatic muscle weakness and autonomic symptoms characterize the autoimmune Lambert-Eaton myasthenic syndrome (LEMS). The former results from IgG autoantibody-mediated down-regulation of P/Q-type voltage-gated calcium channels at motor nerve terminals and consequent reduction in acetylcholine release; the basis for the autonomic symptoms is unknown. Using omega-conotoxins GVIA and MVIIC and omega-agatoxin IVA that block N-, Q-, and P-type channels, we investigated ex vivo the calcium channels subserving transmitter release from postganglionic parasympathetic neurons in the bladder and from postganglionic sympathetic neurons in the vas deferens of mice injected with IgG from LEMS patients or from controls. Calcium influx through N-, P-, and Q-type channels subserved transmitter release from parasympathetic and sympathetic neurons in control mice. In test mice, the component of transmitter release subserved by P-type channels was abolished by four of four LEMS IgG preparations, that subserved by Q-type channels was significantly reduced by three, and that subserved by N-type channels by one. Thus, LEMS IgG impairs transmitter release from parasympathetic and sympathetic neurons through down-regulation of one or more subtypes of voltage-gated calcium channels. The results suggest that antibody-mediated interference with specific ion channel function may also underlie autonomic dysfunction occurring in other autoimmune diseases.
Waterman
S A
SA
University Department of Pharmacology, Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, UK.
Lang
B
B
Newsom-Davis
J
J
D000109:Acetylcholine / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D001341:Autonomic Nervous System / Q000187:drug effects / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D066298:In Vitro Techniques; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D020866:omega-Conotoxin GVIA; D020960:omega-Conotoxins
D001323:Autoantibodies; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007074:Immunoglobulin G; D010455:Peptides; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D020866:omega-Conotoxin GVIA; D000109:Acetylcholine