Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2017 Jun 27;11426:6836-6841. doi: 10.1073/pnas.1621263114.
Show Gene links
Show Anatomy links
Pharmacology of the Nav1.1 domain IV voltage sensor reveals coupling between inactivation gating processes.
Osteen JD
,
Sampson K
,
Iyer V
,
Julius D
,
Bosmans F
.
???displayArticle.abstract???
The Nav1.1 voltage-gated sodium channel is a critical contributor to excitability in the brain, where pathological loss of function leads to such disorders as epilepsy, Alzheimer's disease, and autism. This voltage-gated sodium (Nav) channel subtype also plays an important role in mechanical pain signaling by primary afferent somatosensory neurons. Therefore, pharmacologic modulation of Nav1.1 represents a potential strategy for treating excitability disorders of the brain and periphery. Inactivation is a complex aspect of Nav channel gating and consists of fast and slow components, each of which may involve a contribution from one or more voltage-sensing domains. Here, we exploit the Hm1a spider toxin, a Nav1.1-selective modulator, to better understand the relationship between these temporally distinct modes of inactivation and ask whether they can be distinguished pharmacologically. We show that Hm1a inhibits the gating movement of the domain IV voltage sensor (VSDIV), hindering both fast and slow inactivation and leading to an increase in Nav1.1 availability during high-frequency stimulation. In contrast, ICA-121431, a small-molecule Nav1.1 inhibitor, accelerates a subsequent VSDIV gating transition to accelerate entry into the slow inactivated state, resulting in use-dependent block. Further evidence for functional coupling between fast and slow inactivation is provided by a Nav1.1 mutant in which fast inactivation removal has complex effects on slow inactivation. Taken together, our data substantiate the key role of VSDIV in Nav channel fast and slow inactivation and demonstrate that these gating processes are sequential and coupled through VSDIV. These findings provide insight into a pharmacophore on VSDIV through which modulation of inactivation gating can inhibit or facilitate Nav1.1 function.
Ahern,
The hitchhiker's guide to the voltage-gated sodium channel galaxy.
2016, Pubmed
Ahern,
The hitchhiker's guide to the voltage-gated sodium channel galaxy.
2016,
Pubmed
Bezanilla,
How membrane proteins sense voltage.
2008,
Pubmed
Capes,
Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels.
2013,
Pubmed
,
Xenbase
Capes,
Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor.
2012,
Pubmed
Carter,
Transient sodium current at subthreshold voltages: activation by EPSP waveforms.
2012,
Pubmed
Catterall,
NaV1.1 channels and epilepsy.
2010,
Pubmed
Cestèle,
Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects.
2013,
Pubmed
Cestèle,
Self-limited hyperexcitability: functional effect of a familial hemiplegic migraine mutation of the Nav1.1 (SCN1A) Na+ channel.
2008,
Pubmed
Cha,
Voltage sensors in domains III and IV, but not I and II, are immobilized by Na+ channel fast inactivation.
1999,
Pubmed
,
Xenbase
Chanda,
Tracking voltage-dependent conformational changes in skeletal muscle sodium channel during activation.
2002,
Pubmed
,
Xenbase
Chen,
A unique role for the S4 segment of domain 4 in the inactivation of sodium channels.
1996,
Pubmed
,
Xenbase
Edrich,
State-dependent block of human cardiac hNav1.5 sodium channels by propafenone.
2005,
Pubmed
Escayg,
Sodium channel SCN1A and epilepsy: mutations and mechanisms.
2010,
Pubmed
Escoubas,
Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies.
2002,
Pubmed
Fan,
Early-onset familial hemiplegic migraine due to a novel SCN1A mutation.
2016,
Pubmed
Gargus,
Novel mutation confirms seizure locus SCN1A is also familial hemiplegic migraine locus FHM3.
2007,
Pubmed
Ghovanloo,
Physiology and Pathophysiology of Sodium Channel Inactivation.
2016,
Pubmed
Gilchrist,
Crystallographic insights into sodium-channel modulation by the β4 subunit.
2013,
Pubmed
,
Xenbase
Gilchrist,
Nav1.1 modulation by a novel triazole compound attenuates epileptic seizures in rodents.
2014,
Pubmed
,
Xenbase
Hilber,
Interaction between fast and ultra-slow inactivation in the voltage-gated sodium channel. Does the inactivation gate stabilize the channel structure?
2002,
Pubmed
,
Xenbase
Hoshi,
Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.
1991,
Pubmed
,
Xenbase
Jurkat-Rott,
Voltage-sensor sodium channel mutations cause hypokalemic periodic paralysis type 2 by enhanced inactivation and reduced current.
2000,
Pubmed
Kahlig,
Divergent sodium channel defects in familial hemiplegic migraine.
2008,
Pubmed
Kontis,
Sodium channel inactivation is altered by substitution of voltage sensor positive charges.
1997,
Pubmed
,
Xenbase
Kühn,
Movement of voltage sensor S4 in domain 4 is tightly coupled to sodium channel fast inactivation and gating charge immobilization.
1999,
Pubmed
,
Xenbase
McCormack,
Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels.
2013,
Pubmed
Mitrovic,
Role of domain 4 in sodium channel slow inactivation.
2000,
Pubmed
Ogiwara,
Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation.
2007,
Pubmed
Osteen,
Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.
2016,
Pubmed
Rudy,
Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance.
1978,
Pubmed
Sheets,
The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4.
1999,
Pubmed
Silva,
Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4.
2013,
Pubmed
,
Xenbase
Silva,
Slow inactivation of Na(+) channels.
2014,
Pubmed
Stafstrom,
Persistent sodium current and its role in epilepsy.
2007,
Pubmed
Tai,
Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome.
2014,
Pubmed
Trimmer,
Localization of voltage-gated ion channels in mammalian brain.
2004,
Pubmed
Wang,
A mutation in segment I-S6 alters slow inactivation of sodium channels.
1997,
Pubmed
Wang,
State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine.
2008,
Pubmed
Wang,
Tryptophan scanning of D1S6 and D4S6 C-termini in voltage-gated sodium channels.
2003,
Pubmed
West,
A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.
1992,
Pubmed
,
Xenbase
