A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.

Chen, L Q; Santarelli, Vincent P.; Horn, Richard; Kallen, Roland G.

doi:10.1085/jgp.108.6.549

Cited by 189 publications

(262 citation statements)

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“…6A). The first step initiates fast inactivation and corresponds to the transition of VSDIV from the resting state to the activated state, a step that accounts for the majority of gating charge movement (15,(32)(33)(34)(35). The second, more weakly voltage-dependent, transition moves the activated VSDIV to an immobilized state that is coupled to selectivity filter collapse and slow inactivation, as has been proposed for other voltage-gated channels (14,17,36).…”

Section: Resultsmentioning

confidence: 79%

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Osteen

Sampson

Iyer

et al. 2017

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

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Significance Na v 1.1 is a potential therapeutic target for brain disorders, such as epilepsy, Alzheimer's disease, and autism. Moreover, this voltage-gated sodium (Na v ) channel subtype contributes to mechanical pain by regulating excitability in a specific subset of sensory neurons within the peripheral nervous system. The results of our study shed light on the molecular mechanisms underlying Na v 1.1 inactivation and suggest pharmacologic approaches to address relevant disease-related phenotypes.

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Section: Resultsmentioning

confidence: 79%

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Osteen

Sampson

Iyer

et al. 2017

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

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“…L1433R apparently destabilizes an inactivated conformation, since it (a) increases "rh, (b) decreases the time constant for recovery from inactivation ('r~v), and (c) shifts the steady state inactivation to more depolarized voltages. We postulate that the D4/$3 segment interacts with D4/$4, which is thought to play a more direct role in activation-to-inactivation coupling (Chahine et al, 1994;Keynes, 1994;Chen et al, 1995). Mutations of L1433 may, therefore, affect inactivation by influencing the voltage-dependent conformational transitions of D4/$4.…”

Section: L1433r and R1448c Mutations Affect Hskm1 Inactivation Differmentioning

confidence: 98%

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

George

Horn

et al. 1996

The Journal of General Physiology

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Mutations in the gene encoding the voltage-gated sodium channel of skeletal muscle (SkM1) have been identified in a group of autosomal dominant diseases, characterized by abnormalities of the sarcolemmal excitability, that include paramyotonia congenita (PC) and hyperkalemic periodic paralysis (HYPP). We previously reported that PC mutations cause in common a slowing of inactivation in the human SkM1 sodium channel. In this investigation, we examined the molecular mechanisms responsible for the effects of L1433R, located in D4/$3, on channel gating by creating a series of additional mutations at the 1433 site. Unlike the R1448C mutation, found in D4/$4, which produces its effects largely due to the loss of the positive charge, change of the hydropathy of the side chain rather than charge is the primary factor mediating the effects of L1433R. These two mutations also differ in their effects on recovery from inactivation, conditioned inactivation, and steady state inactivation of the hSkM1 channels. We constructed a double mutation containing both L1433R and R1448C. The double mutation closely resembled R1448C with respect to alterations in the kinetics of inactivation during depolarization and voltage dependence, but was indistinguishable from L1433R in the kinetics of recovery from inactivation and steady state inactivation. No additive effects were seen, suggesting that these two segments interact during gating. In addition, we found that these mutations have different effects on the delay of recovery from inactivation and the kinetics of the tail currents, raising a question whether this delay is a reflection of the deactivation process. These results suggest that the $3 and $4 segments play distinct roles in different processes of hSkM1 channel gating: D4/$4 is critical for the deactivation and inactivation of the open channel while D4/$3 has a dominant role in the recovery of inactivated channels. However, these two segments interact during the entry to, and exit from, inactivation states.

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“…The fast-inactivation process was shown to be coupled to the outward movement of the voltage sensor in DIV (Chen et al, 1996; Cha et al, 1999; Kühn and Greeff, 1999;Sheets et al, 1999), which leads to occlusion of the pore by the inactivation particle Rohl et al, 1999) from the intracellular side in a hinged-lid mechanism a few milliseconds after channel activation (Vassilev et al, 1988;Stühmer et al, 1989;Patton et al, 1992).…”

Section: +mentioning

confidence: 99%

Evolution of voltage-gated ion channels at the emergence of Metazoa

Moran

Barzilai

Liebeskind

et al. 2015

Journal of Experimental Biology

129

116

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Voltage-gated ion channels are large transmembrane proteins that enable the passage of ions through their pore across the cell membrane. These channels belong to one superfamily and carry pivotal roles such as the propagation of neuronal and muscular action potentials and the promotion of neurotransmitter secretion in synapses. In this review, we describe in detail the current state of knowledge regarding the evolution of these channels with a special emphasis on the metazoan lineage. We highlight the contribution of the genomic revolution to the understanding of ion channel evolution and for revealing that these channels appeared long before the appearance of the first animal. We also explain how the elucidation of channel selectivity properties and function in non-bilaterian animals such as cnidarians (sea anemones, corals, jellyfish and hydroids) can contribute to the study of channel evolution. Finally, we point to open questions and future directions in this field of research. KEY WORDS: Voltage-gated ion channels, Animal evolution, Ion selectivity Introduction: the superfamily of voltage-gated ion channelsThis review aims to cover and clarify the evolution and diversification of metazoan voltage-gated ion channels, particularly at the beginning of multicellularity in the lineage leading to Metazoa and at the emergence of nervous systems. Voltage-gated ion channels are imperative for neuronal signaling, muscle contraction and secretion, and are thought to play a critical role in the evolution of animals (Hille, 2001). Nonetheless, these channels are also found in prokaryotes and viruses, although their roles in these organisms are largely unknown (Martinac et al., 2008;Plugge et al., 2000). The superfamily of voltage-gated ion channels is characterized by the ability to rapidly respond to changes in membrane potential (hence 'voltage-gated'), which results in selective ion conductance. This ion channel superfamily includes voltage-gated potassium channels (K V s), voltage-gated calcium channels (Ca V s) and voltage-gated sodium channels (Na V s). Their α-subunits are composed of four domains (DI-IV), with each domain containing six transmembrane segments (S1-S6; Fig. 1) (Noda et al., 1984;Noda et al., 1986;Guy and Seetharamulu, 1986;Tanabe et al., 1987). Voltage-dependent activation is enabled by conserved positively charged residues at every third position in S4 (voltage sensor) of the four domains, which move outwards upon changes in membrane potential (Noda et al., 1984; Catterall, 1986;Guy and Seetharamulu, 1986), inducing a conformational change that results in opening of the channel pore (Armstrong and Bezanilla, 1974;Stühmer et al., 1989;Papazian et al., 1991;Yang et al., 1996). The pore is formed by the segments S5 and S6, and the selectivity to specific ions is enabled by the selectivity filter, which is composed of conserved residues, specific for the ion conducted by the channel, and these residues are situated at the pore-lining loops (p-loops) connecting S5 to S6 in the four domains ( ...

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A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.

Cited by 189 publications

References 33 publications

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

Evolution of voltage-gated ion channels at the emergence of Metazoa

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A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.

Cited by 189 publications

References 33 publications

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Paramyotonia congenita mutations reveal different roles for segments S3 and S4 of domain D4 in hSkM1 sodium channel gating.

Evolution of voltage-gated ion channels at the emergence of Metazoa

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Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes