Molecular Basis of Charge Movement in Voltage-Gated Sodium Channels

Yang, Naibo; George, Alfred L.; Horn, Richard

doi:10.1016/s0896-6273(00)80028-8

Cited by 578 publications

(558 citation statements)

References 39 publications

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“…S5 and S6 in each domain are connected via a P (pore)-segment that lines the outer pore of the ion channel [Fozzard and Hanck, 1996]. Three fundamental gating processes characterize the Na v 1.5 channel [Yang et al, 1996]: activation, fast inactivation, and slow inactivation. Activation is a process whereby the channel opens and Na 1 enters the cell; it is the basic biophysical process behind the cardiac depolarization.…”

Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

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Section: Brs1-mutations In Scn5amentioning

confidence: 99%

The genetic basis of Brugada syndrome: A mutation update

et al. 2009

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“…Moreover, in this Ca 2+ concentration interval, the channel can be maximally activated by voltage, indicating that in the absence of Ca 2+ , voltages high enough can increase the P o to its maximum value . In voltage-dependent channels, membrane depolarization promotes the displacement of the charged residues contained in the S4-inducing gating currents (Armstrong and Bezanilla, 1973;Schneider and Chandler, 1973;Keynes and Rojas, 1974;Yang and Horn, 1995;Aggarwal and MacKinnon, 1996;Seoh et al, 1996;Larsson et al, 1996;Yang et al, 1996;Yusaf et al, 1996;Ahern and Horn, 2004). Gating currents in BK channels were detected by Stefani et al, (1997) in the absence of Ca 2+ and showed that like the G(V) curves, the gating charge-voltage (Q(V)) curves were left-shifted in the presence of Ca 2+ .…”

Section: Sensing Elementsmentioning

confidence: 99%

Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

2006

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Large conductance Ca 2+ -activated K + (BK) channels belong to the S4 superfamily of K + channels that include voltage-dependent K + (Kv) channels characterized by having six (S1-S6) transmembrane domains and a positively charged S4 domain. As Kv channels, BK channels contain a S4 domain, but they have an extra (S0) transmembrane domain that leads to an external NH 2 -terminus. The BK channel is activated by internal Ca 2+ , and using chimeric channels and mutagenesis, three distinct Ca 2+ -dependent regulatory mechanisms with different divalent cation selectivity have been identified in its large COOH-terminus. Two of these putative Ca 2+ -binding domains activate the BK channel when cytoplasmic Ca 2+ reaches micromolar concentrations, and a low Ca 2+ affinity mechanism may be involved in the physiological regulation by Mg 2+ . The presence in the BK channel of multiple Ca 2+ -binding sites explains the huge Ca 2+ concentration range (0.1 μM-100 μM) in which the divalent cation influences channel gating. BK channels are also voltage-dependent, and all the experimental evidence points toward the S4 domain as the domain in charge of sensing the voltage. Calcium can open BK channels when all the voltage sensors are in their resting configuration, and voltage is able to activate channels in the complete absence of Ca 2+ . Therefore, Ca 2+ and voltage act independently to enhance channel opening, and this behavior can be explained using a two-tiered allosteric gating mechanism.

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“…The voltage sensitivity of these channels is derived from a transmembrane ␣-helical segment that contains a cluster of four to eight positively charged amino acids (lysine or arginine). The charged residues form a dipole that moves outward in response to membrane depolarization 7,8 and thereby influences the probability of adopting the closed or open conformation. This cluster of positive charges is in the so-called S4-segment, the fourth of six membranespanning segments in the canonical architecture of a channel subunit in the voltage-gated superfamily (FIG.…”

Section: Voltage-gated Ion Channelsmentioning

confidence: 99%

Physiologic Principles Underlying Ion Channelopathies

Cannon

2007

Neurotherapeutics

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Summary:The ion channelopathies are a diverse array of human disorders caused by mutations in genes coding for ion channels. More than 40 different channelopathies have been identified, with representative disorders from every major class of ion channel and affecting all electrically excitable tissues: brain, peripheral nerve, skeletal muscle, smooth muscle, and heart. This review provides an overview of ion channel classification, structure, and function as a framework for understanding which ion channel properties are altered by disease-associated mutations and how these changes disrupt cellular excitability for channelopathies affecting skeletal muscle and the CNS.

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Molecular Basis of Charge Movement in Voltage-Gated Sodium Channels

Cited by 578 publications

References 39 publications

The genetic basis of Brugada syndrome: A mutation update

The genetic basis of Brugada syndrome: A mutation update

Large conductance Ca2+-activated K+ (BK) channel: Activation by Ca2+ and voltage

Physiologic Principles Underlying Ion Channelopathies

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