Lambert-Eaton Antibodies Inhibit Ca super(2+) Currents But Paradoxically Increase Exocytosis during Stimulus Trains in Bovine Adrenal Chromaffin Cells

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that affects neurotransmitter release at peripheral synapses. LEMS antibodies inhibit Ca super(2+) currents in excitable cells, but it is not known whether there are additional effects on stimulus-secretion coupling. The effect of LEMS antibodies on Ca super(2+) 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 Ca super(2+) current components to different extents. The reduction in Ca super(2+) current resulted in smaller exocytotic responses to single depolarizing pulses, but the normal relationship between integrated Ca super(2+) 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 Ca super(2+)-exocytosis relationship. Enhancement during trains occurs most frequently when pulses are brief and evoke very small amounts of Ca super(2+) entry (Engisch et al., 1997). LEMS antibody treatment increased the percentage of trains eliciting enhancement through two mechanisms: (1) by reducing Ca super(2+) entry and (2) through a Ca super(2+)-independent effect on the process of enhancement. This leads to a paradoxical increase in the amount of exocytosis during stimulus trains, despite inhibition of Ca super(2+ )currents.