Structure and function of voltage‐gated sodium channels

Marbán, Eduardo; Yamagishi, Toshio; Tomaselli, Gordon F.

doi:10.1111/j.1469-7793.1998.647bp.x

Cited by 304 publications

(202 citation statements)

References 100 publications

(57 reference statements)

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“…In mammalian brain, the ␣ subunit associates with auxiliary ␤ subunits of 33-36 kDa (1,6,7). The ␣ subunit contains four homologous domains (I-IV), each containing six predicted transmembrane ␣-helices (S1-S6) and an additional membrane-reentrant pore loop (1,4,5). The S6 segments of each homologous domain are arranged in a square array surrounding the inner pore, whereas the membrane-reentrant pore loops between the S5 and S6 segments line the narrower outer pore and form the ion selectivity filter (1,4,5).…”

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confidence: 99%

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Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ Channel α Subunit

Yarov‐Yarovoy¹,

Brown²,

Sharp³

et al. 2001

Journal of Biological Chemistry

229

203

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Mutations of amino acid residues in the inner twothirds of the S6 segment in domain III of the rat brain type IIA Na ؉ channel (G1460A to I1473A) caused periodic positive and negative shifts in the voltage dependence of activation, consistent with an ␣-helix having one face on which mutations to alanine oppose activation. Mutations in the outer one-third of the IIIS6 segment all favored activation. Mutations in the inner half of IIIS6 had strong effects on the voltage dependence of inactivation from closed states without effect on open-state inactivation. Only three mutations had strong effects on block by local anesthetics and anticonvulsants. Mutations L1465A and I1469A decreased affinity of inactivated Na ؉ channels up to 8-fold for the anticonvulsant lamotrigine and its congeners 227c89, 4030w92, and 619c89 as well as for the local anesthetic etidocaine. N1466A decreased affinity of inactivated Na ؉ channels for the anticonvulsant 4030w92 and etidocaine by 3-and 8-fold, respectively, but had no effect on affinity of the other tested compounds. Leu-1465, Asn-1466, and Ile-1469 are located on one side of the IIIS6 helix, and mutation of each caused a positive shift in the voltage dependence of activation. Evidently, these amino acid residues face the lumen of the pore, contribute to formation of the high-affinity receptor site for pore-blocking drugs, and are involved in voltage-dependent activation and coupling to closed-state inactivation.

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“…Voltage-gated Na ϩ channels are responsible for the initiation and propagation of action potentials in nerve, heart, and skeletal muscle (1)(2)(3)(4)(5). The major structural component of voltage-gated Na ϩ channels is a 260-kDa ␣ subunit, which forms the voltage-gated, Na ϩ -selective pore.…”

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confidence: 99%

Molecular Determinants of Voltage-dependent Gating and Binding of Pore-blocking Drugs in Transmembrane Segment IIIS6 of the Na+ Channel α Subunit

Yarov‐Yarovoy¹,

Brown²,

Sharp³

et al. 2001

Journal of Biological Chemistry

229

203

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“…The ␣-subunit forms the ion pore and is responsible for the voltage-sensitive characteristics of the complex. There are multiple isoforms of the ␣-subunit expressed in different regions of the brain and peripheral nervous system that differ in their kinetic properties (1). The ␤-subunits are auxiliary components acting in a regulatory capacity (7).…”

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confidence: 99%

“…T he voltage-sensitive sodium channel plays a fundamental role in excitable cells, transiently increasing the sodium permeability of the plasma membrane in response to changes in membrane potential and thus propagating the action potential (1,2). Not surprisingly, mutations in sodium channel genes are implicated in several pathologies, including epilepsy and cardiac arrhythmias (3)(4)(5), and therapeutic drugs, including antiepileptics, local anesthetics, and anticonvulsants (6), act on the channel.…”

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confidence: 99%

β3: An additional auxiliary subunit of the voltage-sensitive sodium channel that modulates channel gating with distinct kinetics

Morgan

Stevens

Shah

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

280

297

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The voltage-sensitive sodium channel confers electrical excitability on neurons, a fundamental property required for higher processes including cognition. The ion-conducting ␣-subunit of the channel is regulated by two known auxiliary subunits, ␤1 and ␤2. We have identified rat and human forms of an additional subunit, ␤3. It is most closely related to ␤1 and is the product of a separate gene localized to human chromosome 11q23.3. When expressed in Xenopus oocytes, ␤3 inactivates sodium channel opening more slowly than ␤1 does. Structural modeling has identified an amino acid residue in the putative ␣-subunit binding site of ␤3 that may play a role in this difference. The expression of ␤3 within the central nervous system differs significantly from ␤1. Our results strongly suggest that ␤3 performs a distinct neurophysiological function.T he voltage-sensitive sodium channel plays a fundamental role in excitable cells, transiently increasing the sodium permeability of the plasma membrane in response to changes in membrane potential and thus propagating the action potential (1, 2). Not surprisingly, mutations in sodium channel genes are implicated in several pathologies, including epilepsy and cardiac arrhythmias (3-5), and therapeutic drugs, including antiepileptics, local anesthetics, and anticonvulsants (6), act on the channel.In the central nervous system, the channel is conventionally described as a heterotrimer composed of a 260-kDa ␣-subunit, a noncovalently associated 36-kDa ␤1-subunit, and a disulfidelinked 33-kDa ␤2-subunit (2). The ␣-subunit forms the ion pore and is responsible for the voltage-sensitive characteristics of the complex. There are multiple isoforms of the ␣-subunit expressed in different regions of the brain and peripheral nervous system that differ in their kinetic properties (1). The ␤-subunits are auxiliary components acting in a regulatory capacity (7). ␤1 increases the fraction of ␣-subunits operating in a fast gating mode, thus accelerating the activation and inactivation kinetics of the channel and modulating the frequency with which neurons fire (8). The ␤2-subunit is required for the efficient assembly of the channel but has minor effects on gating kinetics. These two ␤-subunits are distantly related by sequence (9).We now report the cloning and analysis of the rat and human forms of a previously uncharacterized sequence that we call ␤3. It is homologous to ␤1, but differs from ␤1 both in its distribution within the brain and in some of its kinetic properties. The discovery of this subunit increases the complexity of the sodium channel and raises further questions about the role of these auxiliary subunits. Materials and MethodsCloning Methodology. We isolated a variant of the rat pheochromocytoma cell line PC12 (termed A35C), which lacks typical neuronal properties (10). To discover previously unidentified neuroendocrine-specific genes, subtractive cloning was used to identify transcripts expressed at a level in the variant cells lower than that in normal PC12 cells. Total RNA wa...

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“…We turn to examine the interacti on of phenol derivatives with inactivation-deficient congenita [59], or secondary damage, such as denervati on [67], hypoxia or ischaemia [53,68]. Although the diseases differ in their origin and clinical picture, the subsequent alterations in channel gating are surprisingly uniform, comprising a delay in the time-course of channel inactivation which leads to altered membrane excitabili ty.…”

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confidence: 99%