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Article: Molecular Pathology of Sodium Channel Beta-Subunit Variants.

Angsutararux, Paweorn / Zhu, Wandi / Voelker, Taylor L / Silva, Jonathan R

2021 Volume 12, Page(s) 761275

Abstract: The voltage-gated ... ...

Abstract	The voltage-gated Na
Language	English
Publishing date	2021-11-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.761275
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Article ; Online: Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation.

Angsutararux, Paweorn / Kang, Po Wei / Zhu, Wandi / Silva, Jonathan R

The Journal of general physiology

2021 Volume 153, Issue 9

Abstract: Voltage-gated Na+ (NaV) channels underlie the initiation and propagation of action potentials (APs). Rapid inactivation after NaV channel opening, known as open-state inactivation, plays a critical role in limiting the AP duration. However, NaV channel ... ...

Abstract	Voltage-gated Na+ (NaV) channels underlie the initiation and propagation of action potentials (APs). Rapid inactivation after NaV channel opening, known as open-state inactivation, plays a critical role in limiting the AP duration. However, NaV channel inactivation can also occur before opening, namely closed-state inactivation, to tune the cellular excitability. The voltage-sensing domain (VSD) within repeat IV (VSD-IV) of the pseudotetrameric NaV channel α-subunit is known to be a critical regulator of NaV channel inactivation. Yet, the two processes of open- and closed-state inactivation predominate at different voltage ranges and feature distinct kinetics. How inactivation occurs over these different ranges to give rise to the complexity of NaV channel dynamics is unclear. Past functional studies and recent cryo-electron microscopy structures, however, reveal significant inactivation regulation from other NaV channel components. In this Hypothesis paper, we propose that the VSD of NaV repeat III (VSD-III), together with VSD-IV, orchestrates the inactivation-state occupancy of NaV channels by modulating the affinity of the intracellular binding site of the IFMT motif on the III-IV linker. We review and outline substantial evidence that VSD-III activates in two distinct steps, with the intermediate and fully activated conformation regulating closed- and open-state inactivation state occupancy by altering the formation and affinity of the IFMT crevice. A role of VSD-III in determining inactivation-state occupancy and recovery from inactivation suggests a regulatory mechanism for the state-dependent block by small-molecule anti-arrhythmic and anesthetic therapies.
MeSH term(s)	Action Potentials ; Cryoelectron Microscopy ; Kinetics ; Sodium
Chemical Substances	Sodium (9NEZ333N27)
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202112891
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Article ; Online: Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors.

Angsutararux, Paweorn / Dutta, Amal K / Marras, Martina / Abella, Carlota / Mellor, Rebecca L / Shi, Jingyi / Nerbonne, Jeanne M / Silva, Jonathan R

The Journal of general physiology

2023 Volume 155, Issue 5

Abstract: Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I-IV) and forms a macromolecular complex with multiple ... ...

Abstract	Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials. In the heart, the predominant NaV1.5 α subunit is composed of four homologous repeats (I-IV) and forms a macromolecular complex with multiple accessory proteins, including intracellular fibroblast growth factors (iFGF). In spite of high homology, each of the iFGFs, iFGF11-iFGF14, as well as the individual iFGF splice variants, differentially regulates NaV channel gating, and the mechanisms underlying these differential effects remain elusive. Much of the work exploring iFGF regulation of NaV1.5 has been performed in mouse and rat ventricular myocytes in which iFGF13VY is the predominant iFGF expressed, whereas investigation into NaV1.5 regulation by the human heart-dominant iFGF12B is lacking. In this study, we used a mouse model with cardiac-specific Fgf13 deletion to study the consequences of iFGF13VY and iFGF12B expression. We observed distinct effects on the voltage-dependences of activation and inactivation of the sodium currents (INa), as well as on the kinetics of peak INa decay. Results in native myocytes were recapitulated with human NaV1.5 heterologously expressed in Xenopus oocytes, and additional experiments using voltage-clamp fluorometry (VCF) revealed iFGF-specific effects on the activation of the NaV1.5 voltage sensor domain in repeat IV (VSD-IV). iFGF chimeras further unveiled roles for all three iFGF domains (i.e., the N-terminus, core, and C-terminus) on the regulation of VSD-IV, and a slower time domain of inactivation. We present here a novel mechanism of iFGF regulation that is specific to individual iFGF isoforms and that leads to distinct functional effects on NaV channel/current kinetics.
MeSH term(s)	Mice ; Rats ; Humans ; Animals ; Sodium Channels/metabolism ; Action Potentials/physiology ; Protein Isoforms/metabolism ; Myocytes, Cardiac/metabolism ; Fibroblast Growth Factors/genetics ; Fibroblast Growth Factors/metabolism
Chemical Substances	Sodium Channels ; Protein Isoforms ; Fibroblast Growth Factors (62031-54-3)
Language	English
Publishing date	2023-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202213300
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Article ; Online: Arrhythmia-associated calmodulin variants interact with KCNQ1 to confer aberrant membrane trafficking and function.

Kang, Po Wei / Woodbury, Lucy / Angsutararux, Paweorn / Sambare, Namit / Shi, Jingyi / Marras, Martina / Abella, Carlota / Bedi, Anish / Zinn, DeShawn / Cui, Jianmin / Silva, Jonathan R

PNAS nexus

2023 Volume 2, Issue 11, Page(s) pgad335

Abstract: Missense variants in calmodulin (CaM) predispose patients to arrhythmias associated with high mortality rates ("calmodulinopathy"). As CaM regulates many key cardiac ion channels, an understanding of disease mechanism associated with CaM variant ... ...

Abstract	Missense variants in calmodulin (CaM) predispose patients to arrhythmias associated with high mortality rates ("calmodulinopathy"). As CaM regulates many key cardiac ion channels, an understanding of disease mechanism associated with CaM variant arrhythmias requires elucidating individual CaM variant effects on distinct channels. One key CaM regulatory target is the KCNQ1 (K
Language	English
Publishing date	2023-10-14
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgad335
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Article: Arrhythmia-associated Calmodulin Variants Interact with KCNQ1 to Confer Aberrant Membrane Trafficking and Function.

Kang, Po Wei / Woodbury, Lucy / Angsutararux, Paweorn / Sambare, Namit / Shi, Jingyi / Marras, Martina / Abella, Carlota / Bedi, Anish / Zinn, DeShawn / Cui, Jianmin / Silva, Jonathan R

bioRxiv : the preprint server for biology

2023

Abstract: Rationale: Missense variants in calmodulin (CaM) predispose patients to arrhythmias associated with high mortality rates. As CaM regulates several key cardiac ion channels, a mechanistic understanding of CaM variant-associated arrhythmias requires ... ...

Abstract	Rationale: Missense variants in calmodulin (CaM) predispose patients to arrhythmias associated with high mortality rates. As CaM regulates several key cardiac ion channels, a mechanistic understanding of CaM variant-associated arrhythmias requires elucidating individual CaM variant effect on distinct channels. One key CaM regulatory target is the KCNQ1 (K Objective: To observe how arrhythmia-associated CaM variants affect binding to KCNQ1, channel membrane trafficking, and KCNQ1 function. Methods and results: We combine a live-cell FRET binding assay, fluorescence trafficking assay, and functional electrophysiology to characterize >10 arrhythmia-associated CaM variants effect on KCNQ1. We identify one variant (G114W) that exhibits severely weakened binding to KCNQ1 but find that most other CaM variants interact with similar binding affinity to KCNQ1 when compared to CaM wild-type over physiological Ca Conclusions: This study provides comprehensive functional data that reveal how CaM variants contribute to creating a pro-arrhythmic substrate by causing abnormal KCNQ1 membrane trafficking and current conduction. We find that CaM variant regulation of KCNQ1 is not uniform with effects varying from benign to significant loss of function. This study provides a new approach to collecting details of CaM binding that are key for understanding how CaM variants predispose patients to arrhythmia via the dysregulation of multiple cardiac ion channels.
Language	English
Publishing date	2023-01-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.28.526031
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Article ; Online: Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation.

Clippinger, Sarah R / Cloonan, Paige E / Wang, Wei / Greenberg, Lina / Stump, W Tom / Angsutararux, Paweorn / Nerbonne, Jeanne M / Greenberg, Michael J

The Journal of general physiology

2021 Volume 153, Issue 5

Abstract: Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This ... ...

Abstract	Familial hypertrophic cardiomyopathy (HCM), a leading cause of sudden cardiac death, is primarily caused by mutations in sarcomeric proteins. The pathogenesis of HCM is complex, with functional changes that span scales, from molecules to tissues. This makes it challenging to deconvolve the biophysical molecular defect that drives the disease pathogenesis from downstream changes in cellular function. In this study, we examine an HCM mutation in troponin T, R92Q, for which several models explaining its effects in disease have been put forward. We demonstrate that the primary molecular insult driving disease pathogenesis is mutation-induced alterations in tropomyosin positioning, which causes increased molecular and cellular force generation during calcium-based activation. Computational modeling shows that the increased cellular force is consistent with the molecular mechanism. These changes in cellular contractility cause downstream alterations in gene expression, calcium handling, and electrophysiology. Taken together, our results demonstrate that molecularly driven changes in mechanical tension drive the early disease pathogenesis of familial HCM, leading to activation of adaptive mechanobiological signaling pathways.
MeSH term(s)	Calcium ; Cardiomyopathy, Hypertrophic ; Humans ; Mutation ; Sarcomeres ; Tropomyosin/genetics ; Troponin T/genetics
Chemical Substances	Tropomyosin ; Troponin T ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-04-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3118-5
ISSN	1540-7748 ; 0022-1295
ISSN (online)	1540-7748
ISSN	0022-1295
DOI	10.1085/jgp.202012787
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Article ; Online: Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits

Wandi Zhu / Wei Wang / Paweorn Angsutararux / Rebecca L. Mellor / Lori L. Isom / Jeanne M. Nerbonne / Jonathan R. Silva

JCI Insight, Vol 6, Iss

2021 Volume 15

Abstract: Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional ... ...

Abstract	Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by NaVβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (NaVβ1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that NaVβ1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.
Keywords	Cardiology ; Therapeutics ; Medicine ; R
Subject code	572
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Modulation of the effects of class Ib antiarrhythmics on cardiac NaV1.5-encoded channels by accessory NaVβ subunits.

Zhu, Wandi / Wang, Wei / Angsutararux, Paweorn / Mellor, Rebecca L / Isom, Lori L / Nerbonne, Jeanne M / Silva, Jonathan R

JCI insight

2021 Volume 6, Issue 15

Abstract	Native myocardial voltage-gated sodium (NaV) channels function in macromolecular complexes comprising a pore-forming (α) subunit and multiple accessory proteins. Here, we investigated the impact of accessory NaVβ1 and NaVβ3 subunits on the functional effects of 2 well-known class Ib antiarrhythmics, lidocaine and ranolazine, on the predominant NaV channel α subunit, NaV1.5, expressed in the mammalian heart. We showed that both drugs stabilized the activated conformation of the voltage sensor of domain-III (DIII-VSD) in NaV1.5. In the presence of NaVβ1, the effect of lidocaine on the DIII-VSD was enhanced, whereas the effect of ranolazine was abolished. Mutating the main class Ib drug-binding site, F1760, affected but did not abolish the modulation of drug block by NaVβ1/β3. Recordings from adult mouse ventricular myocytes demonstrated that loss of Scn1b (NaVβ1) differentially affected the potencies of lidocaine and ranolazine. In vivo experiments revealed distinct ECG responses to i.p. injection of ranolazine or lidocaine in WT and Scn1b-null animals, suggesting that NaVβ1 modulated drug responses at the whole-heart level. In the human heart, we found that SCN1B transcript expression was 3 times higher in the atria than ventricles, differences that could, in combination with inherited or acquired cardiovascular disease, dramatically affect patient response to class Ib antiarrhythmic therapies.
MeSH term(s)	Animals ; Anti-Arrhythmia Agents/pharmacology ; Biomarkers, Pharmacological/metabolism ; Electrocardiography/methods ; Heart Atria/metabolism ; Heart Atria/physiopathology ; Heart Ventricles/metabolism ; Heart Ventricles/physiopathology ; Humans ; Lidocaine/pharmacology ; Mice ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; NAV1.5 Voltage-Gated Sodium Channel/metabolism ; Patch-Clamp Techniques ; Ranolazine/pharmacology ; Voltage-Gated Sodium Channel Blockers/pharmacology ; Voltage-Gated Sodium Channel beta-1 Subunit/metabolism
Chemical Substances	Anti-Arrhythmia Agents ; Biomarkers, Pharmacological ; NAV1.5 Voltage-Gated Sodium Channel ; SCN1B protein, human ; Scn1b protein, mouse ; Voltage-Gated Sodium Channel Blockers ; Voltage-Gated Sodium Channel beta-1 Subunit ; Lidocaine (98PI200987) ; Ranolazine (A6IEZ5M406)
Language	English
Publishing date	2021-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.143092
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Article ; Online: Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress.

Angsutararux, Paweorn / Luanpitpong, Sudjit / Issaragrisil, Surapol

Oxidative medicine and cellular longevity

2015 Volume 2015, Page(s) 795602

Abstract: Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Understanding molecular mechanisms of chemotherapy-induced ... ...

Abstract	Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Understanding molecular mechanisms of chemotherapy-induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Although no reliable and effective preventive treatment has become available, numerous evidence demonstrates that chemotherapy-induced cardiotoxicity involves the generation of reactive oxygen species (ROS). This review provides an overview of the roles of oxidative stress in chemotherapy-induced cardiotoxicity using doxorubicin, which is one of the most effective chemotherapeutic agents against a wide range of cancers, as an example. Current understanding in the molecular mechanisms of ROS-mediated cardiotoxicity will be explored and discussed, with emphasis on cardiomyocyte apoptosis leading to cardiomyopathy. The review will conclude with perspectives on model development needed to facilitate further progress and understanding on chemotherapy-induced cardiotoxicity.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Autophagy/drug effects ; Disease Models, Animal ; Extracellular Matrix/metabolism ; Heart/drug effects ; Humans ; Myocardium/metabolism ; Neoplasms/drug therapy ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism
Chemical Substances	Antineoplastic Agents ; Reactive Oxygen Species
Language	English
Publishing date	2015-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2015/795602
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Article ; Online: Hyper-O-GlcNAcylation induces cisplatin resistance via regulation of p53 and c-Myc in human lung carcinoma

Sudjit Luanpitpong / Paweorn Angsutararux / Parinya Samart / Nawin Chanthra / Pithi Chanvorachote / Surapol Issaragrisil

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 13

Abstract: Abstract Aberrant metabolism in hexosamine biosynthetic pathway (HBP) has been observed in several cancers, affecting cellular signaling and tumor progression. However, the role of O-GlcNAcylation, a post-translational modification through HBP flux, in ... ...

Abstract	Abstract Aberrant metabolism in hexosamine biosynthetic pathway (HBP) has been observed in several cancers, affecting cellular signaling and tumor progression. However, the role of O-GlcNAcylation, a post-translational modification through HBP flux, in apoptosis remains unclear. Here, we found that hyper-O-GlcNAcylation in lung carcinoma cells by O-GlcNAcase inhibition renders the cells to apoptosis resistance to cisplatin (CDDP). Profiling of various key regulatory proteins revealed an implication of either p53 or c-Myc in the apoptosis regulation by O-GlcNAcylation, independent of p53 status. Using co-immunoprecipitation and correlation analyses, we found that O-GlcNAcylation of p53 under certain cellular contexts, i.e. high p53 activation, promotes its ubiquitin-mediated proteasomal degradation, resulting in a gain of oncogenic and anti-apoptotic functions. By contrast, O-GlcNAcylation of c-Myc inhibits its ubiquitination and subsequent proteasomal degradation. Gene manipulation studies revealed that O-GlcNAcylation of p53/c-Myc is in part a regulator of CDDP-induced apoptosis. Accordingly, we classified CDDP resistance by hyper-O-GlcNAcylation in lung carcinoma cells as either p53 or c-Myc dependence based on their molecular targets. Together, our findings provide novel mechanisms for the regulation of lung cancer cell apoptosis that could be important in understanding clinical drug resistance and suggest O-GlcNAcylation as a potential target for cancer therapy.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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