Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome

Nakajima, Tadashi; Kaneko, Yoshiaki; Saito, Akihiro; Ota, Masaki; Iijima, Takafumi; Kurabayashi, Masahiko

doi:10.1016/j.hrthm.2015.05.032

Cited by 22 publications

(33 citation statements)

References 34 publications

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“…34,35,43 Na V 1.5 variants in this helix can cause gain or loss of channel function by affecting the inactivation process. [20][21][22][23]37,38 For example, R1629Q has wildtype-like peak current, but causes a leftward shift in steady-state inactivation and an increased inactivation rate. 23 Our DMS assay suggests an overall partial loss of function character that is consistent with these data and the clinical manifestation of Brugada Syndrome 23,44 (Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…In the literature, 3 gain of function variants have been identified in R1623 or R1626 and 3 loss of function variants in R1629 and R1632 (Table 1). [20][21][22][23]37,38 The three previously-studied partial loss of function BrS1 variants all had low Deep Mutational Scan scores (62, 66, and 69). Two of three previously studied gain of function LQT3 variants had elevated Deep Mutational Scan scores (129 and 144), while a third mild gain of function variant had a near-wildtype score (95).…”

Section: A Triple Drug Assay Can Identify Scn5a Loss and Gain Of Funcmentioning

confidence: 94%

“…We measure the effect of 248 variants in the voltage sensor (S4) segment of transmembrane domain IV, a hotspot region known to harbor multiple disease-associated gain and loss of function variants. [20][21][22][23] We identify 40 putative gain of function and 33 putative loss of function variants, 8/9 of which were validated by patch clamp data.…”

Section: Introductionmentioning

confidence: 99%

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Deep Mutational Scan of a cardiac sodium channel voltage sensor

Glazer

Kroncke

Matreyek

et al. 2019

Preprint

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Variants in ion channel genes have classically been studied in lowthroughput by patch clamping. Deep Mutational Scanning (DMS) is a complementary approach that can simultaneously assess function of thousands of variants. We have developed and validated a method to perform a DMS of variants in SCN5A, which encodes the major voltage-gated sodium channel in the heart. We created a library of nearly all possible variants in a 36 base region of SCN5A in the S4 voltage sensor of domain IV and stably integrated the library into HEK293T cells. In preliminary experiments, challenge with three drugs (veratridine, brevetoxin, and ouabain) could discriminate wildtype channels from gain and loss of function pathogenic variants. High-throughput sequencing of the pre-and post-drug challenge pools was used to count the prevalence of each variant and identify variants with abnormal function. The DMS scores identified 40 putative gain of function and 33 putative loss of function variants. For 8/9 variants, patch clamping data was consistent with the scores. These experiments demonstrate the accuracy of a high-throughput in vitro scan of SCN5A variant function, which can be used to identify deleterious variants in SCN5A and other ion channel genes.

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Section: Discussionmentioning

confidence: 99%

Section: A Triple Drug Assay Can Identify Scn5a Loss and Gain Of Funcmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Deep Mutational Scan of a cardiac sodium channel voltage sensor

Glazer

Kroncke

Matreyek

et al. 2019

Preprint

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“…Gain-of-function of Na v 1.5 is typically associated with type-3 long QT syndrome (LQT3) [29]. In contrast, loss-of-function of Na v 1.5 can be associated with Brugada syndrome (BrS) [30], sick sinus syndrome (SSS) [31], atrioventricular conduction block [32] and supraventricular tachyarrhythmias (SVTs) [33,34], and these arrhythmic phenotypes can overlap with a single SCN5A mutation.…”

Section: S1 S2 S3 S4 S5 S6mentioning

confidence: 99%

“…Mutations of R1 and R2, R1623Q (R1) and R1626P (R2), commonly exhibited a delayed fast inactivation, which leads to a gain-of-function of Na v 1.5 and can be associated with LQT3 [38][39][40][41]. In contrast, mutations of R3 and R4, such as R1629Q (R3), R1632H (R4) and R1632C (R4), commonly exhibited a marked hyperpolarizing shift in steady-state availability, delayed recovery from inactivation and profound use-dependent current attenuation, resulting in a severe loss-offunction of Na v 1.5 [31,34,42,43]. These functional abnormalities can theoretically be associated with BrS with or without SSS and SVTs.…”

Section: S1 S2 S3 S4 S5 S6mentioning

confidence: 99%

Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

et al. 2019

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The segment 4 (S4) voltage sensor in voltage-gated sodium channels (Na v s) have domain-specific functions, and the S4 segment in domain DIV (DIVS4) plays a key role in the activation and fast inactivation processes through the coupling of arginine residues in DIVS4 with residues of putative gating charge transfer center (pGCTC) in DIVS1-3. In addition, the first four arginine residues (R1-R4) in Na v DIVS4 have position-specific functions in the fast inactivation process, and mutations in these residues are associated with diverse phenotypes of Na v-related diseases (sodium channelopathies). R1 and R2 mutations commonly display a delayed fast inactivation, causing a gain-of-function, whereas R3 and R4 mutations commonly display a delayed recovery from inactivation and profound use-dependent current attenuation, causing a severe loss-offunction. In contrast, mutations of residues of pGCTC in Na v DIVS1-3 can also alter fast inactivation. Such alterations in fast inactivation may be caused by disrupted interactions of DIVS4 with DIVS1-3. Despite fast inactivation of Na v s occurs from both the open-state (open-state inactivation; OSI) and closed state (closed-state inactivation; CSI), changes in CSI have received considerably less attention than those in OSI in the pathophysiology of sodium channelopathies. CSI can be altered by mutations of arginine residues in DIVS4 and residues of pGCTC in Na v s, and altered CSI can be an underlying primary biophysical defect of sodium channelopathies. Therefore, CSI should receive focus in order to clarify the pathophysiology of sodium channelopathies.

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Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

Chen

Wang

et al. 2021

Clinical & Translational Med

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Cardiac voltage‐gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC‐related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life‐threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart‐related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well‐studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.

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Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome

Cited by 22 publications

References 34 publications

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

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Enhanced fast-inactivated state stability of cardiac sodium channels by a novel voltage sensor SCN5A mutation, R1632C, as a cause of atypical Brugada syndrome

Cited by 22 publications

References 34 publications

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Deep Mutational Scan of a cardiac sodium channel voltage sensor

Role of the voltage sensor module in Nav domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation

Ventricular voltage‐gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation

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Product

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Role of the voltage sensor module in Na_v domain IV on fast inactivation in sodium channelopathies: The implication of closed-state inactivation