title: Lambert-Eaton antibodies inhibit Ca2+ currents but paradoxically increase exocytosis during stimulus trains in bovine adrenal chromaffin cells.
abstract: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that affects neurotransmitter release at peripheral synapses. LEMS antibodies inhibit Ca2+ currents in excitable cells, but it is not known whether there are additional effects on stimulus-secretion coupling. The effect of LEMS antibodies on Ca2+ currents and exocytosis was studied in bovine adrenal chromaffin cells using whole-cell voltage clamp in perforated-patch recordings. Purified LEMS IgGs from five patients inhibited N- and P/Q-type Ca2+ current components to different extents. The reduction in Ca2+ current resulted in smaller exocytotic responses to single depolarizing pulses, but the normal relationship between integrated Ca2+ entry and exocytosis (Enisch and Nowycky, 1996) was preserved. The hallmark of LEMS is a large potentiation of neuromuscular transmission after high-frequency stimulation. In chromaffin cells, stimulus trains can induce activity-dependent enhancement of the Ca2+-exocytosis relationship. Enhancement during trains occurs most frequently when pulses are brief and evoke very small amounts of Ca2+ entry (Engisch et al., 1997). LEMS antibody treatment increased the percentage of trains eliciting enhancement through two mechanisms: (1) by reducing Ca2+ entry and (2) through a Ca2+-independent effect on the process of enhancement. This leads to a paradoxical increase in the amount of exocytosis during stimulus trains, despite inhibition of Ca2+ currents.
authors.affiliation: Department of Neurobiology and Anatomy, Medical College of Pennsylvania and Hahnemann University, Philadelphia, Pennsylvania 19129, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Engisch
authors.forename: M M
authors.initials: MM
authors.lastname: Rich
authors.forename: N
authors.initials: N
authors.lastname: Cook
authors.forename: M C
authors.initials: MC
authors.lastname: Nowycky
mesh_terms: D000313:Adrenal Medulla / Q000166:cytology / Q000502:physiology*; D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000494:pharmacology*; D015220:Calcium Channels / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D019439:Chromaffin Cells / Q000166:cytology / Q000502:physiology*; D005071:Evoked Potentials; D005089:Exocytosis; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology*; D015624:Lambert-Eaton Myasthenic Syndrome / Q000097:blood / Q000276:immunology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008875:Middle Aged; D009469:Neuromuscular Junction / Q000276:immunology / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D020866:omega-Conotoxin GVIA
chemical_list: D001323:Autoantibodies; D015220:Calcium Channels; D007074:Immunoglobulin G; D010455:Peptides; D020866:omega-Conotoxin GVIA