Insights into Distinct Modulation of α7 and α7β2 Nicotinic Acetylcholine Receptors by the Volatile Anesthetic Isoflurane |
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Authors: | David D Mowrey Qiang Liu Vasyl Bondarenko Qiang Chen Edom Seyoum Yan Xu Jie Wu Pei Tang |
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Institution: | From the Departments of ‡Anesthesiology.;‖Structural Biology.;§Computational and Systems Biology, and ;**Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260 and ;the ¶Division of Neurology, Barrow Neurological Institute, St. Joseph''s Hospital and Medical Center, Phoenix, Arizona 85013 |
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Abstract: | Nicotinic acetylcholine receptors (nAChRs) are targets of general anesthetics, but functional sensitivity to anesthetic inhibition varies dramatically among different subtypes of nAChRs. Potential causes underlying different functional responses to anesthetics remain elusive. Here we show that in contrast to the α7 nAChR, the α7β2 nAChR is highly susceptible to inhibition by the volatile anesthetic isoflurane in electrophysiology measurements. Isoflurane-binding sites in β2 and α7 were found at the extracellular and intracellular end of their respective transmembrane domains using NMR. Functional relevance of the identified β2 site was validated via point mutations and subsequent functional measurements. Consistent with their functional responses to isoflurane, β2 but not α7 showed pronounced dynamics changes, particularly for the channel gate residue Leu-249(9′). These results suggest that anesthetic binding alone is not sufficient to generate functional impact; only those sites that can modulate channel dynamics upon anesthetic binding will produce functional effects. |
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Keywords: | Anesthetics Cys-loop Receptors Electrophysiology Nicotinic Acetylcholine Receptors NMR Protein Dynamics α 7 α 7β 2 Isoflurane |
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