Modified ligand-gated ion channels and methods of use
AssigneeHoward Hughes Medical Institute
InventorsScott Sternson, Peter Lee, Christopher Magnus
Life of this patent
Estimating the term…
Abstract
This document relates to materials and methods for controlling ligand gated ion channel (LGIC) activity. For example, modified LGICs including at least one LGIC subunit having a modified ligand binding domain (LBD) and/or a modified ion pore domain (IPD) are provided. Also provided are exogenous LGIC ligands that can bind to and activate the modified LGIC, as well as methods of modulating ion transport across the membrane of a cell of a mammal, methods of modulating the excitability of a cell in a mammal, and methods of treating a mammal having a channelopathy.
Claims30
A modified ligand gated ion channel (LGIC) comprising at least one modified LGIC subunit, said modified LGIC subunit comprising:
- a) a modified alph7 nicotinic acetylcholine receptor (α7-nAChR) ligand binding domain (LBD), and wherein said modified α7-nAChR LBD comprises a sequence having at least 85 percent sequence identity to a sequence set forth in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:11;
- and comprises an amino acid substitution at amino acid residue 131 as numbered in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:11;
- and
- b) an ion pore domain (IPD).
A modified ligand gated ion channel (LGIC) comprising five LGIC subunits, wherein at least one LGIC subunit is a chimeric LGIC subunit comprising:
- a) a modified alpha7 nicotinic acetylcholine receptor (α7-nAChR) ligand binding domain (LBD) having an amino acid substitution at residue 131 as numbered in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:11;
- and
- b) a serotonin 3 receptor (5HT3) ion pore domain;
- wherein an exogenous ligand selectively binds to and activates the modified LGIC, wherein the exogenous ligand is a quinuclidine, varenicline, tropisetron, or granisetron;
- and
- wherein the modified LGIC has reduced potency for activation with endogenous acetylcholine relative to a LGIC lacking said chimeric LGIC subunit.
A modified ligand gated ion channel (LGIC) comprising five LGIC subunits, wherein at least one LGIC subunit is a chimeric LGIC subunit comprising:
- a) a modified alphα7 nicotinic acetylcholine receptor (α7-nAChR) ligand binding domain (LBD) having an amino acid substitution at residue 131 as numbered in SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:11;
- and
- b) a glycine receptor (GlyR) ion pore domain;
- wherein an exogenous ligand selectively binds to and activates the modified LGIC, wherein the exogenous ligand is tropisetron or granisetron;
- and
- wherein the modified LGIC has reduced potency for activation with endogenous acetylcholine relative to a LGIC lacking said chimeric LGIC subunit.
Dependencies are inferred from the claim text.