Factors that interfere with the acetylcholine signaling system have long been implicated in cataract. The authors sought to investigate the nature of the electrical response of the intact rabbit lens to acetylcholine.Membrane potential (Vm) and electrical conductance (Gm) were monitored in the isolated, perifused lens by a technique utilizing two internal microelectrodes.Acetylcholine (100 nM to 1 mM) induced a decrease in membrane conductance and a depolarization of membrane potential in the intact lens. The responses were reversed by application of the muscarinic antagonist, atropine (1 microM to 100 microM). In the presence of 1 microM thapsigargin and 30 microM cyclopiazonic acid, acetylcholine still induced an electrical response. Long exposures to acetylcholine induced sustained oscillations of Vm in 10 of 29 lenses (34%). Oscillations were blocked by atropine and the L-type Ca2+ channel blocker nifedipine (10 microM) but were potentiated by thapsigargin.The rabbit lens expressed muscarinic receptors that when activated modulate ionic conductances and cause membrane potential oscillations throughout the tissue. Ca2+ influx rather than primary release from intracellular stores appeared to play a major role in the oscillatory response to acetylcholine.