The alpha7-type nicotinic acetylcholine receptor (nAChR) was recently found to be both fully activated and desensitized by choline, in addition to ACh. In order to understand the combined effects of the two agonists on alpha7 nAChR-mediated neuronal signaling, the kinetics of the receptor-channel's interaction with ACh and choline was examined. To this end, whole-cell and single-channel currents evoked by fast-switching pulses of the agonists were recorded in rat hippocampal neurons in culture. Currents evoked by equieffective concentrations of choline and ACh were very similar, except that choline-evoked currents decayed more quickly to the baseline after removal of the agonist, and that recovery from desensitization was faster with choline. The conductance of channels activated by choline and ACh was 91.5+/-8.5 and 82.9+/-11.6 pS, respectively. The mean apparent channel open times were close to 100 micros, with both agonists. After a 4-s exposure to concentrations up to 80 microM ACh or 600 microM choline, the extent of desensitization and the cumulative charge flow carried by the channels increased in the same proportion, until reaching a maximum. At higher concentrations of either agonist, the cumulative charge started decreasing with concentration, reflecting further desensitization. Kinetic modeling suggested that alpha7 nAChRs have at least two non-equivalent paths to desensitized states, and that choline dissociates faster than ACh from the receptor. Our results established that the main difference between choline and ACh is of affinity, and support the concept that the switching of endogenous agonist may change the desensitization-resensitization dynamics of alpha7 nAChRs.