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Molecular Pharmacology

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Research ArticleArticle

Allosterically Potentiated α7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium

Douglas R. Miller, Habibeh Khoshbouei, Sumanta Garai, Lucas N. Cantwell, Clare Stokes, Ganesh Thakur and Roger L. Papke
Molecular Pharmacology December 2020, 98 (6) 695-709; DOI: https://doi.org/10.1124/molpharm.120.000012
Douglas R. Miller
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Habibeh Khoshbouei
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Sumanta Garai
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Lucas N. Cantwell
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Clare Stokes
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Ganesh Thakur
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Roger L. Papke
Departments of Neuroscience (D.R.M., H.K.) and Pharmacology and Therapeutics (C.S., R.L.P.), University of Florida, Gainesville, Florida; and Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts (S.G., L.N.C., G.T.)
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Abstract

The currents of α7 nicotinic acetylcholine receptors activated by acetylcholine (ACh) are brief. The channel has high permeability to calcium relative to monovalent cations and shows inward rectification. It has been previously noted that in the presence of positive allosteric modulators (PAMs), currents through the channels of α7 receptors differ from normal α7 currents both in sensitivity to specific channel blockers and their current-voltage (I-V) relationships, no longer showing inward rectification. Linear I-V functions are often associated with channels lacking calcium permeability, so we measured the I-V functions of α7 receptors activated by ACh when PAMs were bound to the allosteric binding site in the transmembrane domain. Currents were recorded in chloride-free Ringer’s solution with low or high concentrations of extracellular calcium to determine the magnitude of the reversal potential shift in the two conditions as well as the I-V relationships. ACh-evoked currents potentiated by the allosteric agonist–PAMs (ago-PAMs) (3aR,4S,9bS)-4-(4-bromophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (GAT107) and 3-(3,4-difluorophenyl)-N-(1-(6-(4-(pyridin-2-yl)piperazin-1-yl)pyrazin-2-yl)ethyl)propenamide (B-973B) showed reduced inward rectification and calcium-dependent reversal potential shifts decreased by 80%, and 50%, respectively, compared with currents activated by ACh alone, indicative of reduced calcium permeability. Currents potentiated by 3a,4,5,9b-tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide were also linear and showed no calcium-dependent reversal potential shifts. The ago-PAMs GAT-107 and B-973B stimulated increases in intracellular calcium in stably transfected HEK293 cells. However, these calcium signals were delayed relative to channel activation produced by these agents and were insensitive to the channel blocker mecamylamine. Our results indicate that, although allosterically activated α7 nicotinic ACh receptor may affect intracellular calcium levels, such effects are not likely due to large channel-dependent calcium influx.

SIGNIFICANCE STATEMENT Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptor can increase channel activation by two or more orders of magnitude, raising the concern that, due to the relatively high calcium permeability of α7 receptors activated by acetylcholine alone, such efficacious PAMs may have cytotoxic side effects. We show that PAMs alter the ion conduction pathway and, in general, reduce the calcium permeability of the channels. This supports the hypothesis that α7 effects on intracellular calcium may be independent of channel-mediated calcium influx.

Footnotes

    • Received March 18, 2020.
    • Accepted September 10, 2020.
  • This research was supported by National Institutes of Health Institute of General Medical Sciences [Grant GM57481] (to C.S. and R.L.P.), National Institute on Drug abuse [Grant DA026947] (to H.K. and D.R.M.), National Institute of Neurologic Disorders and Stroke [Grant NS071122] (to D.R.M.), and National Eye Institute [Grant EY024717] (to S.G., L.N.C., and G.T.).

  • https://doi.org/10.1124/molpharm.120.000012.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 98 (6)
Molecular Pharmacology
Vol. 98, Issue 6
1 Dec 2020
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Research ArticleArticle

Calcium Permeability of Potentiated α7 nAChR

Douglas R. Miller, Habibeh Khoshbouei, Sumanta Garai, Lucas N. Cantwell, Clare Stokes, Ganesh Thakur and Roger L. Papke
Molecular Pharmacology December 1, 2020, 98 (6) 695-709; DOI: https://doi.org/10.1124/molpharm.120.000012

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Research ArticleArticle

Calcium Permeability of Potentiated α7 nAChR

Douglas R. Miller, Habibeh Khoshbouei, Sumanta Garai, Lucas N. Cantwell, Clare Stokes, Ganesh Thakur and Roger L. Papke
Molecular Pharmacology December 1, 2020, 98 (6) 695-709; DOI: https://doi.org/10.1124/molpharm.120.000012
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