Nicotinic acetylcholine receptors in autonomic ganglia

Abstract

Although alpha3beta4 subunit combination is clearly prevalent in the nAChRs of autonomic ganglia neurons, the ganglia are strikingly different in the ratio of neurons containing each particular nAChR subunit, as found with immunohistochemical methods and from the analysis of the effects of nAChR subunit-specific antibodies on the ACh-induced membrane currents. In particular, the number of neurons containing alpha3, alpha4, alpha5 or alpha7 subunits is by about three times higher in sympathetic ganglia than in parasympathetic ganglia. This difference may explain why the parasympathetic and sympathetic ganglia markedly differ in their pharmacology. Still, alpha7 subunit makes the highest contribution to ACh-induced membrane current. No correlation between the physiological functions of the ganglia and subunit composition of their nAChRs has been found as yet. High permeability for Ca2+ should permit the nAChRs with alpha7 subunits to influence a variety of Ca2+-dependent events in autonomic neurons. As found with biochemical methods and site-directed mutagenesis, the ACh binding site is formed in the alpha/beta subunits interface by multiple loops containing cysteine, tyrosine and tryptophan amino residues as important for ACh binding. Likewise, both alpha and beta subunits are important for the effects of blocking agents on nAChRs. As found by electrophysiological methods, each neuron of sympathetic and parasympathetic ganglia, as a rule, possesses nAChRs of two groups, "fast" and "slow", with the mean duration of the burst of single channel openings ranging approximately from 5 to 10 and from 25 to 45 ms, respectively. These groups of channels differ from each other with their pharmacology. The burst-like activity of autonomic nAChRs channels is possible only if the disulfide bonds are left intact, otherwise only single openings of the channel are observed. The ionic channel of a nAChRs pentamer is formed by M2 transmembrane segments arranging glutamate, serine, threonine, leucine, and valine rings critical for channel conductance and ionic selectivity. In particular, the mutations V251T and E237A, and insertion of proline or alanine, convert a cation-selective channel into an anion-selective one. The open-channel blockers bind to the nAChR channel at the level where the channel diameter is nearly 12 A, both for "fast" and "slow" channel groups.