Mechanism of action of lead on neuromuscular junctions.
Effects of bath-applied lead acetate on nerve-evoked and spontaneous neurotransmitter release were studied at the neuromuscular junction of the rat using conventional microelectrode recording techniques. Lead (20, 100 microM) depressed end-plate potential (EPP) amplitude within 5 min of application without affecting miniature end-plate potential (MEPP) amplitude. Increasing bath Ca2+ concentration from 2 mM to 4 or 8 mM caused a concentration-dependent reversal of lead-induced block of nerve-evoked EPPs. When lead was washed out of the bath, EPP amplitude either returned to control values, or was potentiated. Mean quantal content (m) was reduced significantly by lead treatment, an effect due primarily to a decrease in the immediately available store of transmitter (n). The probability of transmitter release (p) was either unchanged or slightly increased by lead. In contrast to its depressant effect on evoked transmitter release, spontaneous transmitter release, as measured by MEPP frequency, was increased by lead. MEPP frequency was increased from control levels of 1.2-3.2/sec to 12-16/sec by 100 microM lead. When lead was removed from the bath solution, MEPP frequency returned to control levels. Lead-induced increases in MEPP frequency still occurred when Ca2+ was removed from the external bath solution, or when 1 mM Mn2+ was added to block nerve terminal Ca2+ channels, suggesting that extracellular Ca2+ is not required for lead to increase spontaneous release. It is suggested that lead exerts actions at multiple sites at the presynaptic nerve terminal. An extracellular action of lead on transmitter release mechanisms is likely to be due to a competitive antagonism with Ca2+ for entry through Ca2+ channels. An intracellular action of lead is indicated by the depression of n, and the ability of lead to stimulate spontaneous acetylcholine release in the absence of external Ca2+ entry.
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D007854:Lead / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009045:Motor Endplate / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds; D051381:Rats; D011919:Rats, Inbred Strains
D007473:Ion Channels; D009942:Organometallic Compounds; D007854:Lead; D000109:Acetylcholine; C008261:lead acetate; D002118:Calcium