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Differential Modulation of 2 and 4 Subunits of Human Neuronal Nicotinic Acetylcholine Receptors by Acidification

Department of Pharmacology, Georgetown University School of Medicine, Washington DC (G.A., L.C., M.M.); and Department of Neuroscience, Medical School of the University of Pennsylvania, Philadelphia, Pennsylvania (J.L.)

We have shown previously that acidification increases the affinity of agonists to rat 34 nicotinic acetylcholine receptors (nAChR) and accelerates both the activation and decay kinetics of agonist-induced currents recorded from human embryonic kidney 293 cells stably expressing the receptor (Abdrakhmanova et al., 2002b). Here, we report on experiments examining the effect of rapid acidification on four different subtypes (345, 42, 32, and 325) of human neuronal nAChRs stably expressed in tsA201 cells using a piezoelectric device for rapid (<5 ms) solution application. Application of ACh, at its EC₅₀ concentration for each nAChR subtype, at pH values 7.4 and 6.0, showed that acidification, similarly to that reported for rat 34 acetylcholine receptors (AChRs), increased the amplitude and accelerated the activation and decay kinetics of the currents in human 345 AChRs by increasing their affinity to the agonist. In sharp contrast, acidification reduced the amplitude but accelerated the decay kinetics of the current in all human 2-containing nAChR subtypes (32, 352, 42) examined in this study. Brief application of ACh at saturating concentration (1 mM) on 345 AChRs induced a "rebound current" upon rapid washout of the agonist at pH 7.4, but no "rebound current" was observed in 32 AChRs. Surprisingly, acidification, pH 6.0, applied only during the agonist pulse also accelerated the decay kinetics of the "rebound current". Our data provide evidence for the specificity of proton-induced modulation of neuronal nAChRs based on their subunit composition. Furthermore, in 345 AChR, we find that protonation effects may persist, after washout of acidic solutions, consistent with proton-induced conformational changes of the receptor.

Address correspondence to: Martin Morad, Department of Pharmacology, Georgetown University School of Medicine, 4000 Reservoir Road Building D, Washington DC 20007. E-mail: moradm{at}georgetown.edu

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