Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors

Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< a...
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Autor*in:	Ana M. Marileo [verfasserIn] César O. Lara [verfasserIn] Anggelo Sazo [verfasserIn] Omayra V. Contreras [verfasserIn] Gabriel González [verfasserIn] Patricio A. Castro [verfasserIn] Luis G. Aguayo [verfasserIn] Gustavo Moraga-Cid [verfasserIn] Jorge Fuentealba [verfasserIn] Carlos F. Burgos [verfasserIn] Gonzalo E. Yévenes [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Schlagwörter:	glycine receptor GABA electrophysiology bioinformatics

Übergeordnetes Werk:	In: International Journal of Molecular Sciences - MDPI AG, 2003, 25(2024), 6, p 3390
Übergeordnetes Werk:	volume:25 ; year:2024 ; number:6, p 3390

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc Journal toc

DOI / URN:	10.3390/ijms25063390

Katalog-ID:	DOAJ100493009

Internformat


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520			\|a Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
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allfields	10.3390/ijms25063390 doi (DE-627)DOAJ100493009 (DE-599)DOAJ8a082b33ea804e3886cf93e8c5d645b9 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Ana M. Marileo verfasserin aut Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry César O. Lara verfasserin aut Anggelo Sazo verfasserin aut Omayra V. Contreras verfasserin aut Gabriel González verfasserin aut Patricio A. Castro verfasserin aut Luis G. Aguayo verfasserin aut Gustavo Moraga-Cid verfasserin aut Jorge Fuentealba verfasserin aut Carlos F. Burgos verfasserin aut Gonzalo E. Yévenes verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 6, p 3390 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:6, p 3390 https://doi.org/10.3390/ijms25063390 kostenfrei https://doaj.org/article/8a082b33ea804e3886cf93e8c5d645b9 kostenfrei https://www.mdpi.com/1422-0067/25/6/3390 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 6, p 3390
spelling	10.3390/ijms25063390 doi (DE-627)DOAJ100493009 (DE-599)DOAJ8a082b33ea804e3886cf93e8c5d645b9 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Ana M. Marileo verfasserin aut Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry César O. Lara verfasserin aut Anggelo Sazo verfasserin aut Omayra V. Contreras verfasserin aut Gabriel González verfasserin aut Patricio A. Castro verfasserin aut Luis G. Aguayo verfasserin aut Gustavo Moraga-Cid verfasserin aut Jorge Fuentealba verfasserin aut Carlos F. Burgos verfasserin aut Gonzalo E. Yévenes verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 6, p 3390 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:6, p 3390 https://doi.org/10.3390/ijms25063390 kostenfrei https://doaj.org/article/8a082b33ea804e3886cf93e8c5d645b9 kostenfrei https://www.mdpi.com/1422-0067/25/6/3390 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 6, p 3390
allfields_unstemmed	10.3390/ijms25063390 doi (DE-627)DOAJ100493009 (DE-599)DOAJ8a082b33ea804e3886cf93e8c5d645b9 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Ana M. Marileo verfasserin aut Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry César O. Lara verfasserin aut Anggelo Sazo verfasserin aut Omayra V. Contreras verfasserin aut Gabriel González verfasserin aut Patricio A. Castro verfasserin aut Luis G. Aguayo verfasserin aut Gustavo Moraga-Cid verfasserin aut Jorge Fuentealba verfasserin aut Carlos F. Burgos verfasserin aut Gonzalo E. Yévenes verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 6, p 3390 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:6, p 3390 https://doi.org/10.3390/ijms25063390 kostenfrei https://doaj.org/article/8a082b33ea804e3886cf93e8c5d645b9 kostenfrei https://www.mdpi.com/1422-0067/25/6/3390 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 6, p 3390
allfieldsGer	10.3390/ijms25063390 doi (DE-627)DOAJ100493009 (DE-599)DOAJ8a082b33ea804e3886cf93e8c5d645b9 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Ana M. Marileo verfasserin aut Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry César O. Lara verfasserin aut Anggelo Sazo verfasserin aut Omayra V. Contreras verfasserin aut Gabriel González verfasserin aut Patricio A. Castro verfasserin aut Luis G. Aguayo verfasserin aut Gustavo Moraga-Cid verfasserin aut Jorge Fuentealba verfasserin aut Carlos F. Burgos verfasserin aut Gonzalo E. Yévenes verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 6, p 3390 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:6, p 3390 https://doi.org/10.3390/ijms25063390 kostenfrei https://doaj.org/article/8a082b33ea804e3886cf93e8c5d645b9 kostenfrei https://www.mdpi.com/1422-0067/25/6/3390 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 6, p 3390
allfieldsSound	10.3390/ijms25063390 doi (DE-627)DOAJ100493009 (DE-599)DOAJ8a082b33ea804e3886cf93e8c5d645b9 DE-627 ger DE-627 rakwb eng QH301-705.5 QD1-999 Ana M. Marileo verfasserin aut Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS. <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry César O. Lara verfasserin aut Anggelo Sazo verfasserin aut Omayra V. Contreras verfasserin aut Gabriel González verfasserin aut Patricio A. Castro verfasserin aut Luis G. Aguayo verfasserin aut Gustavo Moraga-Cid verfasserin aut Jorge Fuentealba verfasserin aut Carlos F. Burgos verfasserin aut Gonzalo E. Yévenes verfasserin aut In International Journal of Molecular Sciences MDPI AG, 2003 25(2024), 6, p 3390 (DE-627)316340715 (DE-600)2019364-6 14220067 nnns volume:25 year:2024 number:6, p 3390 https://doi.org/10.3390/ijms25063390 kostenfrei https://doaj.org/article/8a082b33ea804e3886cf93e8c5d645b9 kostenfrei https://www.mdpi.com/1422-0067/25/6/3390 kostenfrei https://doaj.org/toc/1661-6596 Journal toc kostenfrei https://doaj.org/toc/1422-0067 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 25 2024 6, p 3390
language	English
source	In International Journal of Molecular Sciences 25(2024), 6, p 3390 volume:25 year:2024 number:6, p 3390
sourceStr	In International Journal of Molecular Sciences 25(2024), 6, p 3390 volume:25 year:2024 number:6, p 3390
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	<i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics Biology (General) Chemistry
isfreeaccess_bool	true
container_title	International Journal of Molecular Sciences
authorswithroles_txt_mv	Ana M. Marileo @@aut@@ César O. Lara @@aut@@ Anggelo Sazo @@aut@@ Omayra V. Contreras @@aut@@ Gabriel González @@aut@@ Patricio A. Castro @@aut@@ Luis G. Aguayo @@aut@@ Gustavo Moraga-Cid @@aut@@ Jorge Fuentealba @@aut@@ Carlos F. Burgos @@aut@@ Gonzalo E. Yévenes @@aut@@
publishDateDaySort_date	2024-01-01T00:00:00Z
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id	DOAJ100493009
language_de	englisch
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callnumber-first	Q - Science
author	Ana M. Marileo
spellingShingle	Ana M. Marileo misc QH301-705.5 misc QD1-999 misc <i<Gelsemium</i< alkaloids misc glycine receptor misc GABA<sub<A</sub< receptor misc electrophysiology misc bioinformatics misc Biology (General) misc Chemistry Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors
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topic_title	QH301-705.5 QD1-999 Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors <i<Gelsemium</i< alkaloids glycine receptor GABA<sub<A</sub< receptor electrophysiology bioinformatics
topic	misc QH301-705.5 misc QD1-999 misc <i<Gelsemium</i< alkaloids misc glycine receptor misc GABA<sub<A</sub< receptor misc electrophysiology misc bioinformatics misc Biology (General) misc Chemistry
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title	Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors
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title_full	Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors
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author_browse	Ana M. Marileo César O. Lara Anggelo Sazo Omayra V. Contreras Gabriel González Patricio A. Castro Luis G. Aguayo Gustavo Moraga-Cid Jorge Fuentealba Carlos F. Burgos Gonzalo E. Yévenes
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author-letter	Ana M. Marileo
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title_sort	molecular pharmacology of <i<gelsemium</i< alkaloids on inhibitory receptors
callnumber	QH301-705.5
title_auth	Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors
abstract	Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
abstractGer	Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
abstract_unstemmed	Indole alkaloids are the main bioactive molecules of the <i<Gelsemium</i< genus plants. Diverse reports have shown the beneficial actions of <i<Gelsemium</i< alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, <i<Gelsemium</i< alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of <i<Gelsemium</i< alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA<sub<A</sub< receptors (GABA<sub<A</sub<Rs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between <i<Gelsemium</i< alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC<sub<50</sub< of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA<sub<A</sub<Rs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major <i<Gelsemium</i< indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.
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title_short	Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors
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author2	César O. Lara Anggelo Sazo Omayra V. Contreras Gabriel González Patricio A. Castro Luis G. Aguayo Gustavo Moraga-Cid Jorge Fuentealba Carlos F. Burgos Gonzalo E. Yévenes
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Molecular Pharmacology of <i<Gelsemium</i< Alkaloids on Inhibitory Receptors

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