Differential Modulation of Nicotinic Acetylcholine Receptor Subtypes and Synaptic Transmission in Chick Sympathetic Ganglia by PGE2

Abstract

The diversity of neuronal nicotinic acetylcholine receptors (nAChRs) is likely an important factor in the modulation of synaptic transmission by acetylcholine and nicotine. We have tested whether postsynaptic nAChRs are modulated in a subtype-specific manner by prostaglandin E2(PGE2), a regulator of neuronal excitability in both the central and peripheral nervous systems, and examined the effects of PGE2 on nicotinic transmission. Somatodendritic nAChRs in chick lumbar sympathetic ganglia include four nAChR subtypes distinguished on the basis of conductance and kinetic profile. Nanomolar PGE2 applied to the extrapatch membrane differentially regulates opening probability (Po), frequency and the opening duration of each nAChR channel subtype in cell-attached patches. PGE2 decreases the Po of the predominant nAChR subtype (36 pS) and significantly increases Po and open duration of the 23 pS subtype. The 23 pS subtype is gated by the α7-selective agonist choline, and choline-gated currents are inhibited by α-bungarotoxin. To examine whether PGE2modulates nAChRs at synaptic sites, we studied the effects of PGE2 on amplitude and decay of synaptic currents in visceral motoneuron-sympathetic neuron co-cultures. PGE2 significantly decreases the amplitude of miniature excitatory postsynaptic currents (mEPSCs), consistent with the predominant inhibition by PGE2 of all but the 23 pS subtype. The time constant of mEPSCs at PGE2-treated synapses is prolonged, which is also consistent with an increased contribution of the longer open duration of the 23 pS nAChR subtype with PGE2 treatment. To examine the presynaptic effect of PGE2, nanomolar nicotine was used. Nicotine induces facilitation of synaptic transmission by increasing mEPSC frequency, an action thought to involve presynaptic, α7-containing nAChRs. In the presence of PGE2, nicotine-induced synaptic facilitation persists. Thus the net effect of PGE2 is to alter the profile of nAChRs contributing to synaptic transmission from larger conductance, briefer opening channels to smaller conductance, longer opening events. This subtype-specific modulation of nAChRs by PGE2 may provide a mechanism for selective activation and suppression of synaptic pathways mediated by different nAChR subtype(s) at both pre- and postsynaptic sites.