Sulayman D Dib-Hajj

..It has recently been shown that several disease-causing erythromelalgia mutations alter channel-gating behavior in a manner that increases DRG neuron excitability...

..Carbamazepine has been effective in relieving symptoms, while other drugs including other anti-epileptics are less effective...

..9 as particularly important in the pathophysiology of different pain syndromes, and isoform-specific blockers of these channels or targeting their modulators hold the promise of a future effective therapy for treatment of pain...

..Here we review the important functional role of pan-sodium channel and isoform-specific partners in regulating sodium current density and gating properties...

..6 current density. This is the first demonstration of MAPK phosphorylation and modulation of a voltage-gated sodium channel, and this modulation may represent an additional role for MAPK in regulating the neuronal response to injury...

..The preferential expression of FHF2B in sensory neurons may provide a basis for physiological differences in sodium currents that have been reported at the nodes of Ranvier in sensory versus motor axons...

..Our results offer insights into the molecular and cellular mechanisms of modality-specific pain signaling, and suggest Na(v)1.7-blocking drugs may be effective in burn patients...

..6 is necessary for stress-induced current modulation, with positive or negative regulation depending upon the availability of the C-terminal Pro-Ser-Tyr motif to bind Nedd4-2...

..Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Na(v)1.8 current density...

..We propose that the upregulation of contactin and its colocalization with Na(v)1.3 in axotomized DRG neurons may contribute to the hyper-excitablity of the injured neurons...

..Our results suggest that polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain...

....

..7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability...

..7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Na(v)1.7 mutations within intracellular linker parts of the channel have been physiologically characterized...

..7 leads to a pronounced hyperpolarizing shift of activation, a change that is expected to increase nociceptor excitability despite the hyperpolarizing shift in fast-inactivation, which is unique among the IEM mutations...

....

..6 and the Na(+)/Ca(2+) exchanger are colocalized, while selective expression of Na(v)1.2 may support action potential electrogenesis, at least at lower frequencies, while producing a smaller persistent current...

..8, in native neurons, and demonstrates a regulation of Nav1.8 currents that can significantly affect electrogenesis of DRG neurons in which Nav1.8 is normally expressed...

..We conclude that the linker between S4 and S5 in domain I of Nav1.7 modulates gating of this channel, and that a larger side chain at position 241 interferes with its gating mechanisms...

..7 currents. Our results indicate that the firing properties of DRG neurons can be tuned by regulating expression of different sodium channel isoforms that have distinct repriming and closed-state inactivation kinetics...

..6 and are differentially distributed in DRG neurons and their axons. This suggests that FHF2A and FHF2B may selectively alter firing behaviour of specific neuronal compartments via differential modulation of Na(v)1.6...

..8 current in these two DRG subpopulations, which results from their different rate of entry into and recovery from the slow inactivation state, contributes to functional differences between these two neuronal populations...

..7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III...

..7 channels. Continued relief from pain, even after mexiletine was discontinued in this patient, might suggest that early treatment may slow the progression of the disease...

..7 by pERK1/2, which unlike the modulation of Na(v)1.6 and Na(v)1.8 by pp38, regulates gating properties of this channel but not its current density and contributes to the effects of MAPKs on DRG neuron excitability...

....

..This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy...

..In this paper we describe three patients who house the NaV1.7/I228M variant...

..Here, we tested the hypothesis that upregulation of Nav1.8 in cerebellum in MS and EAE has functional consequences contributing to symptom burden...

..Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM...

..Our data provide a pathophysiological basis for the pathogenicity of the first epilepsy-linked mutation within Na(V)1.3 channels and hippocampal neurons...

..These results show that a change in neuronal activity can alter the expression of sodium channel genes in a subtype-specific manner, via a mechanism independent of NGF withdrawal...

..Thus, the ankyrinG-binding motif is both necessary and sufficient for the clustering of sodium channels at nodes of Ranvier and the AIS...

..8 channels. These studies demonstrate that NaV1.8 is an important, direct substrate of PKCε that mediates PKCε-dependent mechanical hyperalgesia...

..CAP-1A thus is the first example of an adapter protein that links clathrin and a sodium channel and may regulate Na(v)1.8 channel density at the cell surface...

....

..These findings led us to hypothesize that Nav1.7 is the main sodium channel in the peripheral olfactory sensory neurons (OSN, also known as olfactory receptor neurons)...

....

..The episodes were triggered by heat or exertion. His medical history revealed an extensive six-generation family history of similar symptoms...

..Although enhanced slow-inactivation may attenuate the gain-of-function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient...

..Although we have used sodium channels for the examples that we show here, these methods can also be used to study other types of molecules...

..Although a functional role for Nav1.9b has yet to be established, intron-to-exon conversion may represent a mechanism for ion channels to acquire novel features...

..The contribution of Na(v)1.7 to acquired and inherited pain states and the absence of motor, cognitive and cardiac deficits in patients lacking this channel make it an attractive target for the treatment of neuropathic pain...

..5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel...

..To provide an overview of the role of voltage-gated sodium channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these channels as therapeutic targets for treating chronic pain...

..We propose that the four aromatic residues contribute to the gate at the cytoplasmic pore aperture, and that their ring side chains form a hydrophobic plug which stabilizes the closed state of Na(v)1.7...

..Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed...

..Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Na(v)1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ)...

..Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain...

..4/1.8C currents demonstrate a non-inactivated fraction. Thus, the C-terminus of Na(v)1.8 contributes to regulation of channel density at the cell surface, modulates channel gating, and regulates the generation of sustained current...

..The central role of Na(v)1.7 in these disorders, and the apparently limited consequences of loss of this channel in humans make it an attractive target for treatment of pain...

..7 and on DRG neuron excitability have not been investigated. We used voltage- and current-clamp recordings to evaluate the hypothesis that ranolazine may be effective in regulating Nav1.7-induced DRG neuron hyperexcitability...

..Our results indicate that Na(v)1.8 underlies electrical activity of sensory neurons subserving multiple functional modalities, and call for cautious interpretation of the phenotypes of Na(v)1.8-Cre-driven conditional knockout mice...

..We suggest that this approach might identify variants that confer enhanced pharmacoresponsiveness on a variety of channels...

....

....

..Taken together, our studies support the contribution of peripheral Na(v)1.3 to pain in adult rats with neuropathic pain, validate Na(v)1.3 as a target, and provide validation for this approach of AAV-mediated peripheral gene therapy...

..7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant Na(V)1.7 that causes pain...

..7 in rat dorsal root ganglia neurons, from peripheral terminals in the skin to central terminals in the spinal cord dorsal horn...

..Implications regarding the presence of these different types of channels and receptors in human red blood cells and their functional significance are discussed...

..Our results should aid the development of toxins that block specific neuronal sodium channel isoforms...

..3 mRNA, with GDNF plus NGF producing the largest effect. Our data indicate that both GDNF and NGF can partially reverse an important effect of axotomy on the electrogenic properties of sensory neurons and that their effect is additive...

..The data provide direct evidence that Na(v)1.9 is expressed selectively in (but not in all) C- and A-fiber nociceptive-type units and suggest that Na(v)1.9 contributes to membrane properties that are typical of nociceptive neurons...

..Therefore, we conclude that the tetrapeptide SLEN at the D4S3-S4 linker region is sufficient to make Na(v)1.8 resistant to LQTX...

..7 and suggests that the response of individuals with hereditary erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype...

....

..6 produce resurgent currents. These results demonstrate for the first time the intrinsic ability of Na(v)1.6 to produce a resurgent current, and also show that cell background is critical in permitting the generation of these currents...

....

..We investigated the role of Na(v)1.7 in a sporadic case of erythermalgia in a Chinese family...