Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.

Inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are homologous cation channels that mediate release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) and thereby are involved in many physiological processes. In previous studies, we determined that when the D2594 r...

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Authors: Tambeaux, Allison, Aguilar-Sánchez, Yuriana, Santiago, Demetrio J, Mascitti, Madeleine, DiNovo, Karyn M, Mejía-Alvarez, Rafael, Fill, Michael, Wayne Chen, S R, Ramos-Franco, Josefina
Format: article
Publication Date:2023
Country:España
Institution:Instituto de Salud Carlos III (ISCIII)
Repository:Repisalud
Language:English
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/16449
Online Access:http://hdl.handle.net/20.500.12105/16449
Access Level:Open access
Keyword:Calcium Signaling
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate Receptors
Ligands
Mutation
Calcium
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spelling Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.Tambeaux, AllisonAguilar-Sánchez, YurianaSantiago, Demetrio JMascitti, MadeleineDiNovo, Karyn MMejía-Alvarez, RafaelFill, MichaelWayne Chen, S RRamos-Franco, JosefinaCalcium SignalingEndoplasmic ReticulumInositol 1,4,5-Trisphosphate ReceptorsLigandsMutationCalciumInositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are homologous cation channels that mediate release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) and thereby are involved in many physiological processes. In previous studies, we determined that when the D2594 residue, located at or near the gate of the IP3R type 1, was replaced by lysine (D2594K), a gain of function was obtained. This mutant phenotype was characterized by increased IP3 sensitivity. We hypothesized the IP3R1-D2594 determines the ligand sensitivity of the channel by electrostatically affecting the stability of the closed and open states. To test this possibility, the relationship between the D2594 site and IP3R1 regulation by IP3, cytosolic, and luminal Ca2+ was determined at the cellular, subcellular, and single-channel levels using fluorescence Ca2+ imaging and single-channel reconstitution. We found that in cells, D2594K mutation enhances the IP3 ligand sensitivity. Single-channel IP3R1 studies revealed that the conductance of IP3R1-WT and -D2594K channels is similar. However, IP3R1-D2594K channels exhibit higher IP3 sensitivity, with substantially greater efficacy. In addition, like its wild type (WT) counterpart, IP3R1-D2594K showed a bell-shape cytosolic Ca2+-dependency, but D2594K had greater activity at each tested cytosolic free Ca2+ concentration. The IP3R1-D2594K also had altered luminal Ca2+ sensitivity. Unlike IP3R1-WT, D2594K channel activity did not decrease at low luminal Ca2+ levels. Taken together, our functional studies indicate that the substitution of a negatively charged residue by a positive one at the channels' pore cytosolic exit affects the channel's gating behavior thereby explaining the enhanced ligand-channel's sensitivity.SpringerNational Institutes of Health (Estados Unidos)Heart and Stroke Foundation20232023-09-1220232023-05-0120232023-05-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/16449reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/164492026-06-12T12:43:37Z
dc.title.none.fl_str_mv Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
title Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
spellingShingle Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
Tambeaux, Allison
Calcium Signaling
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate Receptors
Ligands
Mutation
Calcium
title_short Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
title_full Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
title_fullStr Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
title_full_unstemmed Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
title_sort Ligand sensitivity of type-1 inositol 1,4,5-trisphosphate receptor is enhanced by the D2594K mutation.
dc.creator.none.fl_str_mv Tambeaux, Allison
Aguilar-Sánchez, Yuriana
Santiago, Demetrio J
Mascitti, Madeleine
DiNovo, Karyn M
Mejía-Alvarez, Rafael
Fill, Michael
Wayne Chen, S R
Ramos-Franco, Josefina
author Tambeaux, Allison
author_facet Tambeaux, Allison
Aguilar-Sánchez, Yuriana
Santiago, Demetrio J
Mascitti, Madeleine
DiNovo, Karyn M
Mejía-Alvarez, Rafael
Fill, Michael
Wayne Chen, S R
Ramos-Franco, Josefina
author_role author
author2 Aguilar-Sánchez, Yuriana
Santiago, Demetrio J
Mascitti, Madeleine
DiNovo, Karyn M
Mejía-Alvarez, Rafael
Fill, Michael
Wayne Chen, S R
Ramos-Franco, Josefina
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv National Institutes of Health (Estados Unidos)
Heart and Stroke Foundation
dc.subject.none.fl_str_mv Calcium Signaling
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate Receptors
Ligands
Mutation
Calcium
topic Calcium Signaling
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate Receptors
Ligands
Mutation
Calcium
description Inositol 1,4,5-trisphosphate receptor (IP3R) and ryanodine receptor (RyR) are homologous cation channels that mediate release of Ca2+ from the endoplasmic/sarcoplasmic reticulum (ER/SR) and thereby are involved in many physiological processes. In previous studies, we determined that when the D2594 residue, located at or near the gate of the IP3R type 1, was replaced by lysine (D2594K), a gain of function was obtained. This mutant phenotype was characterized by increased IP3 sensitivity. We hypothesized the IP3R1-D2594 determines the ligand sensitivity of the channel by electrostatically affecting the stability of the closed and open states. To test this possibility, the relationship between the D2594 site and IP3R1 regulation by IP3, cytosolic, and luminal Ca2+ was determined at the cellular, subcellular, and single-channel levels using fluorescence Ca2+ imaging and single-channel reconstitution. We found that in cells, D2594K mutation enhances the IP3 ligand sensitivity. Single-channel IP3R1 studies revealed that the conductance of IP3R1-WT and -D2594K channels is similar. However, IP3R1-D2594K channels exhibit higher IP3 sensitivity, with substantially greater efficacy. In addition, like its wild type (WT) counterpart, IP3R1-D2594K showed a bell-shape cytosolic Ca2+-dependency, but D2594K had greater activity at each tested cytosolic free Ca2+ concentration. The IP3R1-D2594K also had altered luminal Ca2+ sensitivity. Unlike IP3R1-WT, D2594K channel activity did not decrease at low luminal Ca2+ levels. Taken together, our functional studies indicate that the substitution of a negatively charged residue by a positive one at the channels' pore cytosolic exit affects the channel's gating behavior thereby explaining the enhanced ligand-channel's sensitivity.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-09-12
2023
2023-05-01
2023
2023-05-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/16449
url http://hdl.handle.net/20.500.12105/16449
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,198674

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