MONOVALENT AND DIVALENT-CATION PERMEABILITY AND BLOCK OF NEURONAL NICOTINIC RECEPTOR CHANNELS IN RAT PARASYMPATHETIC GANGLIA

Acetylcholine-evoked currents mediated by activation of nicotinic rece ptors in rat parasympathetic neurons were examined using whole-cell vo ltage clamp. The relative permeability of the neuronal nicotinic acety lcholine (nACh) receptor channel to monovalent and divalent inorganic and organic cations was determined from reversal potential measurement s. The channel exhibited weak selectivity among the alkali metals with a selectivity sequence of Cs+ > K+ > Rb+ > Na+ > Li+, and permeabilit y ratios relative to Na+ (P-x/P-Na) ranging from 1.27 to 0.75. The sel ectivity of the alkaline earths was also weak, with the sequence of Mg 2+ > Sr2+ > Ba2+ > Ca2+, and relative permeabilities of 1.10 to 0.65. The relative Ca2+ permeability (P-ca/P-Na) of the neuronal nACh recept or channel is similar to fivefold higher than that of the motor endpla te channel (Adams, D. J., T. M. Dwyer, and B. Hille. 1980. Journal of General Physiology. 75:493-510). The transition metal cation, Mn2+ was permeant (P-x/P-Na = 0.67), whereas Ni2+, Zn2+, and Cd2+ blocked ACh- evoked currents with half-maximal inhibition (IC50) occurring at simil ar to 500 mu M, 5 mu M and 1 mM, respectively. In contrast to the musc le endplate AChR channel, that at least 56 organic cations which are p ermeable to (Dwyer et al., 1980), the majority of organic cations test ed were found to completely inhibit ACh-evoked currents in rat parasym pathetic neurons. Concentration-response curves for guanidinium, ethyl ammonium, diethanolammonium and arginine inhibition of ACh-evoked curr ents yielded IC50's of similar to 2.5-6.0 mM. The organic cations, hyd razinium, methylammonium, ethanolammonium and Tris, were measureably p ermeant, and permeability ratios varied inversely with the molecular s ize of the cation. Modeling suggests that the pore has a minimum diame ter of 7.6 Angstrom. Thus, there are substantial differences in ion pe rmeation and block between the nACh receptor channels of mammalian par asympathetic neurons and amphibian skeletal muscle which represent fun ctional consequences of differences in the primary structure of the su bunits of the ACh receptor channel.