Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]

Publication Date:
2018-02-24
Publisher:
The American Society for Biochemistry and Molecular Biology (ASBMB)
Print ISSN:
0021-9258
Electronic ISSN:
1083-351X
Topics:
Biology
Chemistry and Pharmacology
Published by:
http://www.asbmb.org/
_version_ 1836398810416283648
autor Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
beschreibung Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand-gated ion channels (pLGICs) and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid-photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites, and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand-gated ion channel (GLIC), a prototypic pLGIC. The neurosteroid-based reagents photolabeled two sites per GLIC subunit, both within the transmembrane domain; one site was an intrasubunit site, and the other was located in the interface between subunits. By using reagents with photoreactive groups positioned throughout the neurosteroid backbone, we precisely map the orientation of neurosteroid binding within each site. Amino acid substitutions introduced at either site altered neurosteroid modulation of GLIC channel activity, demonstrating the functional role of both sites. These results provide a detailed molecular model of multisite neurosteroid modulation of GLIC, which may be applicable to other mammalian pLGICs.
citation_standardnr 6174196
datenlieferant ipn_articles
feed_id 43
feed_publisher The American Society for Biochemistry and Molecular Biology (ASBMB)
feed_publisher_url http://www.asbmb.org/
insertion_date 2018-02-24
journaleissn 1083-351X
journalissn 0021-9258
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Biochemistry and Molecular Biology (ASBMB)
quelle Journal of Biological Chemistry
relation http://feedproxy.google.com/~r/jbc/SUcv/~3/vyrn0SnlPH0/3013.short
search_space articles
shingle_author_1 Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
shingle_author_2 Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
shingle_author_3 Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
shingle_author_4 Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
shingle_catch_all_1 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand-gated ion channels (pLGICs) and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid-photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites, and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand-gated ion channel (GLIC), a prototypic pLGIC. The neurosteroid-based reagents photolabeled two sites per GLIC subunit, both within the transmembrane domain; one site was an intrasubunit site, and the other was located in the interface between subunits. By using reagents with photoreactive groups positioned throughout the neurosteroid backbone, we precisely map the orientation of neurosteroid binding within each site. Amino acid substitutions introduced at either site altered neurosteroid modulation of GLIC channel activity, demonstrating the functional role of both sites. These results provide a detailed molecular model of multisite neurosteroid modulation of GLIC, which may be applicable to other mammalian pLGICs.
Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
The American Society for Biochemistry and Molecular Biology (ASBMB)
0021-9258
00219258
1083-351X
1083351X
shingle_catch_all_2 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand-gated ion channels (pLGICs) and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid-photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites, and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand-gated ion channel (GLIC), a prototypic pLGIC. The neurosteroid-based reagents photolabeled two sites per GLIC subunit, both within the transmembrane domain; one site was an intrasubunit site, and the other was located in the interface between subunits. By using reagents with photoreactive groups positioned throughout the neurosteroid backbone, we precisely map the orientation of neurosteroid binding within each site. Amino acid substitutions introduced at either site altered neurosteroid modulation of GLIC channel activity, demonstrating the functional role of both sites. These results provide a detailed molecular model of multisite neurosteroid modulation of GLIC, which may be applicable to other mammalian pLGICs.
Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
The American Society for Biochemistry and Molecular Biology (ASBMB)
0021-9258
00219258
1083-351X
1083351X
shingle_catch_all_3 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand-gated ion channels (pLGICs) and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid-photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites, and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand-gated ion channel (GLIC), a prototypic pLGIC. The neurosteroid-based reagents photolabeled two sites per GLIC subunit, both within the transmembrane domain; one site was an intrasubunit site, and the other was located in the interface between subunits. By using reagents with photoreactive groups positioned throughout the neurosteroid backbone, we precisely map the orientation of neurosteroid binding within each site. Amino acid substitutions introduced at either site altered neurosteroid modulation of GLIC channel activity, demonstrating the functional role of both sites. These results provide a detailed molecular model of multisite neurosteroid modulation of GLIC, which may be applicable to other mammalian pLGICs.
Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
The American Society for Biochemistry and Molecular Biology (ASBMB)
0021-9258
00219258
1083-351X
1083351X
shingle_catch_all_4 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand-gated ion channels (pLGICs) and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid-photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites, and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand-gated ion channel (GLIC), a prototypic pLGIC. The neurosteroid-based reagents photolabeled two sites per GLIC subunit, both within the transmembrane domain; one site was an intrasubunit site, and the other was located in the interface between subunits. By using reagents with photoreactive groups positioned throughout the neurosteroid backbone, we precisely map the orientation of neurosteroid binding within each site. Amino acid substitutions introduced at either site altered neurosteroid modulation of GLIC channel activity, demonstrating the functional role of both sites. These results provide a detailed molecular model of multisite neurosteroid modulation of GLIC, which may be applicable to other mammalian pLGICs.
Wayland W. L. Cheng, Zi-Wei Chen, John R. Bracamontes, Melissa M. Budelier, Kathiresan Krishnan, Daniel J. Shin, Cunde Wang, Xin Jiang, Douglas F. Covey, Gustav Akk, Alex S. Evers
The American Society for Biochemistry and Molecular Biology (ASBMB)
0021-9258
00219258
1083-351X
1083351X
shingle_title_1 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
shingle_title_2 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
shingle_title_3 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
shingle_title_4 Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
timestamp 2025-06-30T23:33:00.026Z
titel Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
titel_suche Mapping two neurosteroid-modulatory sites in the prototypic pentameric ligand-gated ion channel GLIC [Neurobiology]
topic W
V
uid ipn_articles_6174196