In the nervous system, voltage-gated Ca2+ channels regulate numerous processes 
critical to neuronal function including secretion of neurotransmitters, 
initiation of action potentials in dendritic regions of some neurons, growth 
cone elongation, and gene expression. Because of the critical role which Ca2+ 
channels play in signaling processes within the nervous system, disruption of 
their function will lead to profound disturbances in neuronal function. 
Voltage-gated Ca2+ channels are the targets of several relatively rare 
neurological or neuromuscular diseases resulting from spontaneously-occurring 
mutations in genes encoding for parts of the channel proteins, or from 
autoimmune attack on the channel protein responses. Mutations in CACNAIA, which 
encodes for the alpha1A subunit of P/Q-type Ca2+ channels, lead to symptoms seen 
in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar 
ataxia type 6. Conversely, autoimmune attack on Ca2+ channels at motor axon 
terminals causes peripheral cholinergic nerve dysfunction observed in 
Lambert-Eaton Myasthenic Syndrome (LEMS), the best studied of the disorders 
targeting voltage-gated Ca2+ channels. LEMS is characterized by decreased evoked 
quantal release of acetylcholine (ACh) and disruption of the presynaptic active 
zones, the sites at which ACh is thought to be released. LEMS is generally 
believed to be due to circulating antibodies directed specifically at the Ca2+ 
channels located at or near the active zone of motor nerve terminals (P/Q-type) 
and hence involved in the release of ACh. However, other presynaptic proteins 
have also been postulated to be targets of the autoantibodies. LEMS has a high 
degree of coincidence (approximately 60%) with small cell lung cancer; the 
remaining 40% of patients with LEMS have no detectable tumor. Diagnosis of LEMS 
relies on characteristic patterns of electromyographic changes; these changes 
are observable at neuromuscular junctions of muscle biopsies from patients with 
LEMS. In the majority of LEMS patients, those having detectable tumor, the 
disease is thought to occur as a result of immune response directed initially 
against voltage-gated Ca2+ channels found on the lung tumor cells. In these 
patients, effective treatment of the underlying tumor generally causes marked 
improvement of the symptoms of LEMS as well. Animal models of LEMS can be 
generated by chronic administration of plasma, serum or immunoglobulin G to 
mice. These models have helped dramatically in our understanding of the 
pathogenesis of LEMS. This "passive transfer" model mimics the 
electrophysiological and ultrastructural findings seen in muscle biopsies of 
patients with LEMS. In this model, we have shown that the reduction in amplitude 
of Ca2+ currents through P/Q-type channels is followed by "unmasking" of an 
L-type Ca2+ current not normally found at the motor nerve terminal which 
participates in release of ACh from terminals of mice treated with plasma from 
patients with LEMS. It is unclear what mechanisms underlie the development of 
this novel L-type Ca2+ current involved in release of ACh at motor nerve 
terminals during passive transfer of LEMS.