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Michael C Sanguinetti

Publications and source records attributed to Michael C Sanguinetti.

At least 19 recordsLinked to original sources
PubMed2007

Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.

BACKGROUND: Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. METHODS AND RESULTS: Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits. CONCLUSIONS: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

Adult↗
PubMed2006

Binding site of a novel Kv1.5 blocker: a "foot in the door" against atrial fibrillation.

Kv1.5 channel blockers prolong atrial action potentials and may prevent atrial flutter or fibrillation without affecting ventricular repolarization. Here we characterize the mechanisms of action of 2'-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide (AVE0118) on Kv1.5 channels heterologously expressed in Xenopus laevis oocytes. Whole cell currents in oocytes were recorded using the two-microelectrode voltage clamp technique. AVE0118 blocked Kv1.5 current in oocytes with an IC50 of 5.6 microM. Block was enhanced by higher rates of stimulation, consistent with preferential binding of the drug to the open state of the channel. Ala-scanning mutagenesis of the pore domain of Kv1.5 identified the amino acids Thr479, Thr480, Val505, Ile508, Val512, and Val516 as important residues for block by AVE0118. A homology model of the pore region of Kv1.5 predicts that these six residues face toward the central cavity of the channel. In addition, mutation of two other S6 residues (Ile502 and Leu510) that are predicted to face away from the central cavity also diminished drug block. All these putative drug-binding residues are highly conserved in other Kv channels, explaining our finding that AVE0118 also blocked Kv1.3, Kv2.1, Kv3.1, and Kv4.3 channels with similar potency. Docking of AVE0118 into the inner cavity of a Kv1.5 pore homology model predicted an unusual binding mode. The drug aligned with the inner S6 alpha-helical domain in a manner predicted to block the putative activation gate. This "foot-in-the-door" binding mode is consistent with the observation that the drug slowed the rate of current deactivation, causing a crossover of tail current traces recorded before and after drug treatment.

Animals↗
PubMed2006

hERG potassium channels and cardiac arrhythmia.

hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.

Animals↗
PubMed2006

Molecular determinants of HERG channel block.

Drug-induced block of cardiac hERG K+ channels causes acquired long QT syndrome. Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine (E-4031) and dofetilide). Channels were expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. All four drugs progressively reduced hERG current during a 20-s depolarization to 0 mV after a 10-min pulse-free period, consistent with the preferential block of open channels. Recovery from block in response to pulses to -160 mV was observed for D540K hERG channels but not for wild-type hERG channels, suggesting that all four drugs are trapped in the central cavity by closure of the activation gate. The molecular determinants of hERG channel block were defined by using a site-directed mutagenesis approach. Mutation to alanine of three residues near the pore helix (Thr623, Ser624, and Val625) and four residues in Ser6 (Gly648, Tyr652, Phe656, and Val659) reduced channel sensitivity to block by dofetilide and E-4031, effects identical with those reported previously for two other methanesulfonanilides, (+)- N -[1' -(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro(2H -1-benzopyran-2,4' -piperidin)-6-yl]-methanesulfonamide] monohydrochloride (MK-499) and ibutilide. The effect of nifekalant on mutant channels was similar, except that V659A retained normal sensitivity and I655A channels were less sensitive. Finally, mutation of the three residues near the pore helix and Phe656 in the Ser6 domain reduced channel block by bepridil. We conclude that the binding site is not identical for all drugs that preferentially block hERG in the open state.

DNA Primers↗
PubMed2005

Differential roles of S6 domain hinges in the gating of KCNQ potassium channels.

Voltage-gated K+ channel activation is proposed to result from simultaneous bending of all S6 segments away from the central axis, enlarging the aperture of the pore sufficiently to permit diffusion of K+ into the water-filled central cavity. The hinge position for the bending motion of each S6 segment is proposed to be a Gly residue and/or a Pro-Val-Pro motif in Kv1-Kv4 channels. The KCNQ1 (Kv7.1) channel has Ala-336 in the Gly-hinge position and Pro-Ala-Gly. Here we show that mutation of Ala-336 to Gly in KCNQ1 increased current amplitude and shifted the voltage dependence of activation to more negative potentials, consistent with facilitation of hinge activity that favors the open state. In contrast, mutation of Ala-336 to Cys or Thr shifted the voltage dependence of activation to more positive potentials and reduced current amplitude. Mutation of the putative Gly hinge to Ala in KCNQ2 (Kv7.2) abolished channel function. Mutation-dependent changes in current amplitude, but not kinetics, were found in heteromeric KCNQ1/KCNE1 channels. Mutation of the Pro or Gly of the Pro-Ala-Gly motif to Ala abolished KCNQ1 function and introduction of Gly in front of the Ala-mutations partially recovered channel function, suggesting that flexibility at the PAG is important for channel activation.

Amino Acid Sequence↗
PubMed2005

Mechanism of action of a novel human ether-a-go-go-related gene channel activator.

1,3-Bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) is a newly discovered activator of human ether-a-go-go-related gene (hERG) K(+) channels. Here, we characterize the effects of this compound on cloned hERG channels heterologously expressed in Xenopus laevis oocytes. When assessed with 2-s depolarizations, NS1643 enhanced the magnitude of wild-type hERG current in a concentration- and voltage-dependent manner with an EC(50) of 10.4 microM at -10 mV. The fully activated current-voltage relationship revealed that the drug increased outward but not inward currents, consistent with altered inactivation gating. NS1643 shifted the voltage dependence of inactivation by +21 mV at 10 microM and +35 mV at 30 microM, but it did not alter the voltage dependence of activation of hERG channels. The effects of the drug on three inactivation-deficient hERG mutant channels (S620T, S631A, and G628C/S631C) were determined. In the absence of channel inactivation, NS1643 did not enhance hERG current magnitude. The agonist activity of NS1643 was facilitated by mutations (F656 to Val, Met, or Thr) that are known to greatly attenuate channel inhibition by hERG blockers. We conclude that NS1643 is a partial agonist of hERG channels and that the mechanism of activation is reduced channel inactivation.

Animals↗
PubMed2005

De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero.

OBJECTIVE: We describe a genetic basis for atrial fibrillation and short QT syndrome in utero. Heterologous expression of the mutant channel was used to define the physiological consequences of the mutation. METHODS: A baby girl was born at 38 weeks after induction of delivery that was prompted by bradycardia and irregular rythm. ECG revealed atrial fibrillation with slow ventricular response and short QT interval. Genetic analysis identified a de novo missense mutation in the potassium channel KCNQ1 (V141M). To characterize the physiological consequences of the V141M mutation, Xenopus laevis oocytes were injected with cRNA encoding wild-type (wt) KCNQ1 or mutant V141M KCNQ1 subunits, with or without KCNE1. RESULTS: Ionic currents were recorded using standard two-microelectrode voltage clamp techniques. In the absence of KCNE1, wtKCNQ1 and V141M KCNQ1 currents had similar biophysical properties. Coexpression of wtKCNQ1+KCNE1 subunits induced the typical slowly activating and voltage-dependent delayed rectifier K(+) current, I(Ks). In contrast, oocytes injected with cRNA encoding V141M KCNQ1+KCNE1 subunits exhibited an instantaneous and voltage-independent K(+)-selective current. Coexpression of V141M and wtKCNQ1 with KCNE1 induced a current with intermediate biophysical properties. Computer modeling showed that the mutation would shorten action potential duration of human ventricular myocytes and abolish pacemaker activity of the sinoatrial node. CONCLUSIONS: The description of a novel, de novo gain of function mutation in KCNQ1, responsible for atrial fibrillation and short QT syndrome in utero indicates that some of these cases may have a genetic basis and confirms a previous hypothesis that gain of function mutations in KCNQ1 channels can shorten the duration of ventricular and atrial action potentials.

Action Potentials↗
PubMed2005

Structural basis for competition between drug binding and Kvbeta 1.3 accessory subunit-induced N-type inactivation of Kv1.5 channels.

Kvbeta subunits are accessory proteins that modify gating of Kv1 channels. Kvbeta1.3 subunits bind to the N termini of Kv1.5 alpha-subunits and induce fast N-type inactivation, slow the rate of deactivation, and alter the voltage dependence and kinetics of channel activation. The N terminus of a Kvbeta subunit and quaternary ammonium compounds bind to the inner pore of Kv1 channels; however, it is unknown to what extent the pore binding sites for drugs and Kvbeta subunits overlap. Here, we used site-directed Ala mutagenesis to scan residues of the Kv1.5 pore to define the binding site for Kvbeta1.3 subunits. Individual mutations of five residues in the S6 domain (Val505, Ile508, Leu510, Val512, and Val516) greatly retarded or prevented Kvbeta1.3 induced inactivation, and reduced effects on Kv1.5 deactivation. Mutation of Thr479 and Thr480 enhanced Kvbeta1.3-induced N-type inactivation. None of the Ala mutations prevented the Kvbeta1.3-induced negative shifts in the voltage dependence of activation or slow C-type inactivation, suggesting that these gating effects are mediated by an interaction other than the one for N-type inactivation. Thr479, Thr480, Val505, Ile508, and Val512, of Kv1.5 channels are also important interaction sites for the anthranilic acid S0100176 (N-benzyl-N-pyridin-3-ylmethyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride). Leu510 and V516A prevented Kvbeta1.3-induced inactivation but did not alter drug block. Block of Kv1.5 by S0100176 was reduced and voltage-dependent in the presence of Kvbeta1.3 but not in the presence of an N-truncated form of the Kvbeta subunit. Thus, residues in the pore of Kv1.5 required for N-type inactivation overlap with but are not identical to the drug binding site.

Amino Acid Sequence↗
PubMed2005

Molecular mapping of a site for Cd2+-induced modification of human ether-à-go-go-related gene (hERG) channel activation.

Cd(2+) slows the rate of activation, accelerates the rate of deactivation and shifts the half-points of voltage-dependent activation (V(0.5,act)) and inactivation (V(0.5,inact)) of human ether-à-go-go-related gene (hERG) K(+) channels. To identify specific Cd(2+)-binding sites on the hERG channel, we mutated potential Cd(2+)-coordination residues located in the transmembrane domains or extracellular loops linking these domains, including five Cys, three His, nine Asp and eight Glu residues. Each residue was individually substituted with Ala and the resulting mutant channels heterologously expressed in Xenopus oocytes and their biophysical properties determined with standard two-microelectrode voltage-clamp technique. Cd(2+) at 0.5 mM caused a +36 mV shift of V(0.5,act) and a +18 mV shift of V(0.5,inact) in wild-type channels. Most mutant channels had a similar sensitivity to 0.5 mM Cd(2+). Mutation of single Asp residues located in the S2 (D456, D460) or S3 (D509) domains reduced the Cd(2+)-induced shift in V(0.5,act), but not V(0.5,inact). Combined mutations of two or three of these key Asp residues nearly eliminated the shift induced by 0.5 mM Cd(2+). Mutation of D456, D460 and D509 also reduced the comparatively low-affinity effects of Ca(2+) and Mg(2+) on V(0.5,act). Extracellular Cd(2+) modulates hERG channel activation by binding to a coordination site formed, at least in part, by three Asp residues.

Animals↗
PubMed2005

Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations.

Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.

Action Potentials↗
PubMed2005

Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels.

KCNQ1 (Kv 7.1) alpha-subunits and KCNE1 beta-subunits co-assemble to form channels that conduct the slow delayed rectifier K+ current (IKs) in the heart. Mutations in either subunit cause long QT syndrome (LQTS), an inherited disorder of cardiac repolarization. Here, the functional consequences of the LQTS-associated missense mutation V310I and several nearby residues were determined. Val310 is located at the base of the pore helix of KCNQ1, two residues below the TIGYG signature sequence that defines the K+ selectivity filter. Channels were heterologously expressed in Xenopus laevis oocytes and currents were recorded using the two-microelectrode voltage-clamp technique. V310I KCNQ1 reduced IKs amplitude when co-expressed with wild-type KCNQ1 and KCNE1 subunits. Val310 was also mutated to Gly, Ala or Leu to explore the importance of amino acid side chain volume at this position. Like V310I, V310L KCNQ1 channels gated normally. Unexpectedly, V310G and V310A KCNQ1 channels inactivated strongly and did not close normally in response to membrane hyperpolarization. Based on a homology model of the KCNQ1 channel pore, we speculate that the side group of residue 310 can interact with specific residues in the S5 and S6 domains to alter channel gating. When volume of the side chain is small, the stability of the closed state is disrupted and the extent of channel inactivation is enhanced. We mutated putative interacting residues in S5 and S6 and found that mutant Leu273 and Phe340 channels also can disrupt close states and modify inactivation. Together these findings indicate the importance of a putative pore helix-S5-S6 interaction for normal KCNQ1 channel deactivation and confirm its role in KCNQ1 inactivation. Disturbance of these interactions might underly LQTS associated with KCNQ1 mutant channels.

Amino Acid Sequence↗
PubMed2005

Voltage sensor movement in the hERG K+ channel.

The critical role of hERG in the maintenance of normal cardiac electrical activity derives from its unusual gating properties: slow channel activation and fast inactivation. To characterize voltage sensor movement associated with slow activation and fast inactivation, we measured gating currents from wild-type and mutant hERG channels. Fast and slow gating components were observed that differed 100-fold in their kinetics. The slow component constituted the majority of gating charge associated with channel opening and accounted for the sluggish rate of hERG activation. Gating currents from an inactivation-deficient mutant (S631A) were indistinguishable from wild-type, despite a +100 mV shift in the voltage dependence of inactivation, suggesting that a small fraction of total gating charge is devoted to the final transitions that inactivate the channel. Ala-scanning mutagenesis in S4 identified residues that perturbed both charge movement and channel opening. Residues in the S4-S5 linker perturbed channel opening without altering charge displacement, suggesting a role for coupling S4 movement to channel opening. Finally, inactivation-sensitive residues localized to a helical face of S4 adjacent to the activation-sensitive residues. We conclude that S4 acts as the voltage sensor for hERG activation and inactivation and that S4 movement is translated to the activation gate via the S4-S5 linker.

Animals↗
PubMed2005

Predicting drug-hERG channel interactions that cause acquired long QT syndrome.

Avoiding drug-induced cardiac arrhythmia is recognized as a major hurdle in the successful development of new drugs. The most common problem is acquired long QT syndrome caused by drugs that block human ether-a-go-go-related-gene (hERG) K(+) channels, delay cardiac repolarization and increase the risk of torsades de pointes arrhythmia (TdP). Not all hERG channel blockers induce TdP because they can also modulate other channels that counteract the hERG channel-mediated effect. However, hERG channel blockade is an important indicator of potential pro-arrhythmic liability. The molecular determinants of hERG channel blockade have been defined using a site-directed mutagenesis approach. Combined with pharmacophore models, knowledge of the drug-binding site of hERG channels will facilitate in silico design efforts to discover drugs that are devoid of this rare, but potentially lethal, side-effect.

Animals↗
PubMed2005

Structural determinants for high-affinity block of hERG potassium channels.

Drug-induced long QT syndrome is an abnormality of cardiac action potential repolarization that can induce arrhythmias and sudden death. This unwanted side effect of some medications is most frequently associated with block of hERG channels, even though it could theoretically result from inhibition of any K+ current with a role in repolarization. Recent studies suggest an explanation for why so many structurally diverse compounds preferentially block hERG. State dependent inhibition of hERG channel currents and slow kinetics for recovery from block suggest that many drugs bind within the inner cavity of the channel and are trapped by closure of the activation gate upon repolarization. Drug trapping studies indicate that the inner cavity of hERG is larger than other voltage-gated K+ channels. Scanning Ala mutagenesis of S6 and pore helix domains that line the inner cavity of hERG have demonstrated that two aromatic residues (Tyr652 and Phe656) are important sites of interaction for most blockers investigated so far. These residues are unique to the EAG channel family. Ser624 and Thr623 residues at the base of the pore helices are also critical for high-affinity binding for some compounds (e.g. methanesulfonanilides) but not others (cisapride, terfenadine, propafenone).

Action Potentials↗
PubMed2005

Physicochemical basis for binding and voltage-dependent block of hERG channels by structurally diverse drugs.

Blockade of hERG K+ channels in the heart is an unintentional side effect of many drugs and can induce cardiac arrhythmia and sudden death. For this reason, most pharmaceutical companies screen compounds for hERG channel activity early in the drug discovery/development process. A detailed understanding of the drug binding site(s) on the hERG channel could enable rational design of future medications devoid of this unwanted side effect. Towards this goal, we have used site-directed mutagenesis to identify several residues of the hERG channel that comprise a common drug binding site. The initial Ala-scan identified several residues located in the S6 domain (Tyr652, Phe656) and the base of the pore helix (Thr623, Ser624, Val625) as important sites of interaction. Here, we review studies that refine our understanding of the physicochemical basis of interaction by structurally diverse drugs with aromatic residues in the S6 domain. Our findings suggest that the position of Tyr652 and Phe656 in hERG is optimal for interaction with multiple drugs, Tyr652 is an important determinant of voltage-dependent block, and the hydrophobic surface area of residue 656 and aromaticity of residue 652 are the physicochemical features required for high-affinity block by MK-499, cisapride and terfenadine.

Action Potentials↗
PubMed2004

Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine.

Halofantrine is an antimalarial drug developed as a treatment of P. falciparum resistant to chloroquine. However, halofantrine can also induce long QT syndrome (LQTS) and torsades de pointes, a potentially life-threatening ventricular arrhythmia. Drug-induced LQTS is usually caused by block of the human ether-a-go-go-related gene (HERG) channels that conduct the rapid delayed rectifier K(+) current, I(Kr), in the heart. Here we show that halofantrine preferentially blocks open and inactivated HERG channels heterologously expressed in Xenopus laevis oocytes. The half-maximal inhibitory concentration (IC(50)) for block of wild-type (WT) HERG was 1.0 microM. As we reported previously for other HERG channel blockers, the potency of halofantrine was reduced by mutation to Ala of aromatic residues (Y652, F656) located in the S6 domain, or a Val (V625) located in the pore helix. Halofantrine at a concentration 10 microM did not affect the transient outward potassium channel, Kv4.3, the slow delayed rectifier potassium channel, KvLQT1+minK and inward rectifier potassium channel, Kir2.1. An inactivation deficient mutant (G628C/S631C HERG) was only slightly less sensitive (IC(50)=2.0 microM). The rate of block onset by halofantrine at 0 mV was used to estimate the apparent association (k(on)) and dissociation (k(off)) rate constants for drug binding. For WT and G628C/S631C HERG, k(on) was similar (0.0114 and 0.0163 M(-1)/s(-1) respectively). In contrast, k(off) was significantly faster for G628C/S631C (0.357 s(-1)) than WT (0.155 s(-1)), and explains the observed decrease in drug potency for the inactivation-deficient mutant channel. We conclude that halofantrine requires channels to open before it can gain access to its binding site located in the central cavity of the HERG channel.

Animals↗
PubMed2004

Regional specificity of human ether-a'-go-go-related gene channel activation and inactivation gating.

Slow activation and rapid C-type inactivation produce inward rectification of the current-voltage relationship for human ether-a'-go-go-related gene (hERG) channels. To characterize the voltage sensor movement associated with hERG activation and inactivation, we performed an Ala scan of the 32 amino acids (Gly(514)-Tyr(545)) that comprise the S4 domain and the flanking S3-S4 and S4-S5 linkers. Gating and ionic currents of wild-type and mutant channels were measured using cut-open oocyte Vaseline gap and two microelectrode voltage clamp techniques to determine the voltage dependence of charge movement, activation, and inactivation. Mapping the position of the charge-perturbing mutations (defined as |DeltaDeltaG| > 1.0 kcal/mol) on a three-dimensional S4 homology model revealed a spiral pattern. As expected, mutation of these residues also altered activation. However, mutation of residues in the S3-S4 and S4-S5 linkers and the C-terminal end of S4 perturbed activation (|DeltaDeltaG| > 1.0 kcal/mol) without altering charge movement, suggesting that the native residues in these regions couple S4 movement to the opening of the activation gate or stabilize the open or closed state of the channel. Finally, mutation of a distinct set of residues impacted inactivation and mapped to a single face of the S4 helix that was devoid of activation-perturbing residues. These results define regions on the S4 voltage sensor that contribute differentially to hERG activation and inactivation gating.

Amino Acid Sequence↗