LAMBERT-EATON SERA REDUCE LOW-VOLTAGE AND HIGH-VOLTAGE ACTIVATED CA2-ROOT GANGLION NEURONS( CURRENTS IN MURINE DORSAL)

Voltage-gated Ca2+ channels are categorized as either high-voltage act ivated (HVA) or low-voltage activated (LVA), and a subtype (or subtype s) of HVA Ca2+ channels link the presynaptic depolarization to rapid n eurotransmitter release, Reductions in transmitter release are charact eristic of the autoimmune disorder, Lambert-Eaton syndrome (LES). Beca use antibodies from LES patients reduce Ca2+ influx in a variety of ce ll types and disrupt the intramembrane organization of active zones at neuromuscular synapses, specificity of LES antibodies for the Ca2+ ch annels that control transmitter release has been suggested as the mech anism for disease, We tested sera from four patients with LES, Serum s amples from three of the four patients reduced both the maximal LVA an d HVA Ca2+ conductances in murine dorsal root ganglion neurons, Thus, even though LES is expressed as a neuromuscular and autonomic disorder , our studies suggest that Ca2+ channels may be broadly affected in LE S patients, To account for the specificity of disease expression, me s uggest that incapacitation of only a fraction of the Ca2+ channels clu stered at active zones would severely depress transmitter release, In particular, if several Ca2+ channels in a cluster are normally require d to open simultaneously before transmitter release becomes likely, th e loss of a few active zone Ca2+ channels would exponentially reduce t he probability of transmitter release, This model may explain why LES is expressed as a neuromuscular disorder and can account for a clinica l hallmark of LES, facilitation of neuromuscular transmission produced by vigorous voluntary effort.