Na+ Channel ? Subunits: Overachievers of the Ion Channel Family

Brackenbury, William J.; Isom, Lori L.

doi:10.3389/fphar.2011.00053

Cited by 271 publications

(345 citation statements)

References 108 publications

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“…In our experiments, L1649Q was rescued by incubation at 30°C, a typical feature of folding-defective mutants (20), or by coexpression with interacting proteins that can probably stabilize correct folding, a condition closer to real pathophysiological ones. Na + channel principal α subunits are associated with accessory β subunits, and have stable interactions also with several other proteins (26,27). As highlighted previously, accessory β1 or β2 subunits did not rescue L1649Q, differently than for other Na V 1.1 mutants (21,22,24).…”

Section: Significancementioning

confidence: 55%

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Cestèle

Schiavon

Rusconi

et al. 2013

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

137

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Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A, the gene encoding the Na v 1.1 Na + channel, which is also a major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of Na V 1.1 FHM mutations have generated controversial results. In particular, it has been shown that the Na V 1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to Na V 1.1 mutants that cause severe epilepsy, but we have observed gain-offunction effects for other Na V 1.1 FHM mutants. Here we show that Na V 1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic Na V 1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of Na V 1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.spreading depression | Dravet syndrome | generalized epilepsy with febrile seizures plus | calmodulin | ankyrin

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Section: Significancementioning

confidence: 55%

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Cestèle

Schiavon

Rusconi

et al. 2013

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

137

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“…This hyperexcitability mediates enduring changes in the nervous system, contributing to both peripheral and central sensitization (4). Na v s are heteromeric glycosylated protein complexes composed of a large pore-forming α subunit and auxiliary β subunits (5,6). Nine genes encode for distinct channel isoforms (Na v 1.1 to Na v 1.9), each displaying specific properties.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

115

160

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Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Na v s) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na v s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Na v s, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na v 1.7-specific inhibitor, ProTxII, allowed the isolation of Na v 1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na v 1.7 and Na v 1.8 currents. The redistribution of Na v 1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L -/-). SNS-Nedd4L -/-mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na v 1.7 and Na v 1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na v s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

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“…It is well established that voltage-gated channels are not only composed of pore-forming subunits but auxiliary subunits as well, which are not part of the pore, but control many important aspects of channel function, such as trafficking and gating (1,2). In contrast, ligand-gated ion channels were thought to function independently of auxiliary subunits.…”

mentioning

confidence: 99%

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Yamazaki

Pichon²,

Jackson

et al. 2015

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

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Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function. Because γ-2 and γ-7 are both strongly expressed in multiple cell types in the cerebellum, we examined the relative contribution of γ-2 and γ-7 to both synaptic transmission in the cerebellum and motor behavior by using both the stargazer mouse and a γ-7 knockout (KO) mouse. We found that the loss of γ-7 alone had little effect on climbing fiber (cf) responses in Purkinje neurons (PCs), yet the additional loss of γ-2 all but abolished cf responses. In contrast, γ-7 failed to make a significant contribution to excitatory transmission in stellate cells and granule cells. In addition, we generated a PC-specific deletion of γ-2, with and without γ-7 KO background, to examine the relative contribution of γ-2 and γ-7 to PC-dependent motor behavior. Selective deletion of γ-2 in PCs had little effect on motor behavior, yet the additional loss of γ-7 resulted in a severe disruption in motor behavior. Thus, γ-7 is capable of supporting a component of excitatory transmission in PCs, sufficient to maintain essentially normal motor behavior, in the absence of γ-2.cerebellum | AMPA receptors | TARPs | stargazer | motor behavior N euronal excitability is controlled by two broad classes of ion channels: voltage-gated and ligand-gated. It is well established that voltage-gated channels are not only composed of pore-forming subunits but auxiliary subunits as well, which are not part of the pore, but control many important aspects of channel function, such as trafficking and gating (1, 2). In contrast, ligand-gated ion channels were thought to function independently of auxiliary subunits. The discovery of the tetraspanning membrane protein stargazin, also referred to as γ-2, which is mutated in the ataxic stargazer (stg) mouse, changed this view. Cerebellar granule neurons (CGNs), which express high levels of stargazin, were found to lack surface AMPA-type glutamate receptors (AMPARs) in the stg mouse (3, 4). Stargazin not only controls the trafficking of AMPARs, but also controls AMPAR gating (5-10), indicating that it satisfies all of the criteria of auxiliary subunits. Stargazin is a member of a family of proteins referred to as transmembrane AMPAR regulatory proteins (TARPs) and consists of the following members: canonical type I TARPs (γ-2, γ-3, γ-4, and γ-8) and atypical type II TARPs (γ-5 and γ-7), which differ in their amino acid sequence and uniquely regulate AMPAR trafficking, gating, and neuropharmacology (7).Of particular interest is TARP γ-7, which is expressed throughout the brain...

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Na+ Channel ? Subunits: Overachievers of the Ion Channel Family

Cited by 271 publications

References 108 publications

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

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Na+ Channel ? Subunits: Overachievers of the Ion Channel Family

Cited by 271 publications

References 108 publications

Nonfunctional Na V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Nonfunctional Na V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

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Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects