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The Journal of Neuroscience, May 1, 1999, 19(9):3384-3395

Lambert-Eaton Antibodies Inhibit Ca²⁺ Currents But Paradoxically Increase Exocytosis during Stimulus Trains in Bovine Adrenal Chromaffin Cells

Kathrin L. Engisch¹, Mark M. Rich², Noah Cook¹, and Martha C. Nowycky¹

¹ Department of Neurobiology and Anatomy, Medical College of Pennsylvania and Hahnemann University, Philadelphia, Pennsylvania 19129, and ² Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

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 (Engisch 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.

Key words: exocytosis; chromaffin cell; capacitance detection; Ca²⁺-secretion coupling; Lambert-Eaton myasthenic syndrome; facilitation

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1993384-12$05.00/0

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