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Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.

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Title: Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.
Authors: Alcaino, Constanza1, Musgaard, Maria2, Minguez, Teresa1, Mazzaferro, Simone1, Faundez, Manuel3, Iturriaga-Vasquez, Patricio4, Biggin, Philip C.2, Bermudez, Isabel1 ibermudez@brookes.ac.uk
Source: Journal of Biological Chemistry. 1/13/2017, Vol. 292 Issue 2, p551-562. 12p.
Subjects: Acetylcholine-binding proteins, Membrane proteins, Muscarinic agonists, Ligand-gated ion channels, Electrophysiology, Neurotransmitters
Abstract: Allosteric modulators of pentameric ligand-gated ion channels are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pentameric ligand-gated ion channels. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4) region of the α4 subunit. Here, using homology modeling in combination with mutagenesis and electrophysiology, we identified the binding site for potentiating dFBr on the top half of a cavity between the third (M3) and fourth transmembrane (M4) α-helices of the α4 subunit. We found that the binding sites for βEST and dFBr communicate with the Cys loop, through interactions between the last residue of post-M4 and Phe170 of the conserved FPF sequence of the Cys loop, and that these interactions affect potentiating efficacy. In addition, interactions between a residue in M3 (Tyr309) and Phe167, a residue adjacent to the Cys loop FPF motif, also affect dFBr potentiating efficacy. Thus, the Cys loop acts as a key control element in the allosteric transduction pathway for potentiating βEST and dFBr. Overall, we propose that positive allosteric modulators that bind the M3-M4 cavity or post-M4 region increase the efficacy of channel gating through interactions with the Cys loop. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.
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  Data: <searchLink fieldCode="AR" term="%22Alcaino%2C+Constanza%22">Alcaino, Constanza</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Musgaard%2C+Maria%22">Musgaard, Maria</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Minguez%2C+Teresa%22">Minguez, Teresa</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Mazzaferro%2C+Simone%22">Mazzaferro, Simone</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Faundez%2C+Manuel%22">Faundez, Manuel</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Iturriaga-Vasquez%2C+Patricio%22">Iturriaga-Vasquez, Patricio</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Biggin%2C+Philip+C%2E%22">Biggin, Philip C.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Bermudez%2C+Isabel%22">Bermudez, Isabel</searchLink><relatesTo>1</relatesTo><i> ibermudez@brookes.ac.uk</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 1/13/2017, Vol. 292 Issue 2, p551-562. 12p.
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  Data: <searchLink fieldCode="DE" term="%22Acetylcholine-binding+proteins%22">Acetylcholine-binding proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Membrane+proteins%22">Membrane proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Muscarinic+agonists%22">Muscarinic agonists</searchLink><br /><searchLink fieldCode="DE" term="%22Ligand-gated+ion+channels%22">Ligand-gated ion channels</searchLink><br /><searchLink fieldCode="DE" term="%22Electrophysiology%22">Electrophysiology</searchLink><br /><searchLink fieldCode="DE" term="%22Neurotransmitters%22">Neurotransmitters</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Allosteric modulators of pentameric ligand-gated ion channels are thought to act on elements of the pathways that couple agonist binding to channel gating. Using α4β2 nicotinic acetylcholine receptors and the α4β2-selective positive modulators 17β-estradiol (βEST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pentameric ligand-gated ion channels. Previous studies have shown that the binding site for potentiating βEST is in the C-terminal (post-M4) region of the α4 subunit. Here, using homology modeling in combination with mutagenesis and electrophysiology, we identified the binding site for potentiating dFBr on the top half of a cavity between the third (M3) and fourth transmembrane (M4) α-helices of the α4 subunit. We found that the binding sites for βEST and dFBr communicate with the Cys loop, through interactions between the last residue of post-M4 and Phe170 of the conserved FPF sequence of the Cys loop, and that these interactions affect potentiating efficacy. In addition, interactions between a residue in M3 (Tyr309) and Phe167, a residue adjacent to the Cys loop FPF motif, also affect dFBr potentiating efficacy. Thus, the Cys loop acts as a key control element in the allosteric transduction pathway for potentiating βEST and dFBr. Overall, we propose that positive allosteric modulators that bind the M3-M4 cavity or post-M4 region increase the efficacy of channel gating through interactions with the Cys loop. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1074/jbc.M116.751206
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      – Code: eng
        Text: English
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        PageCount: 12
        StartPage: 551
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      – SubjectFull: Acetylcholine-binding proteins
        Type: general
      – SubjectFull: Membrane proteins
        Type: general
      – SubjectFull: Muscarinic agonists
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      – SubjectFull: Ligand-gated ion channels
        Type: general
      – SubjectFull: Electrophysiology
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      – SubjectFull: Neurotransmitters
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      – TitleFull: Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors.
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              M: 01
              Text: 1/13/2017
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