Lidocaine block of neonatal Nav1.3 is differentially modulated by co-expression of β1 and β3 subunits

Lenkowski, Paul W.; Shah, Bhaval S.; Dinn, Andrew E; Lee, Kevin; Patel, Manoj K.

doi:10.1016/s0014-2999(03)01595-4

Cited by 33 publications

(38 citation statements)

References 40 publications

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“…For example, blockage of Na v 1.3 by lidocaine was reduced in a concentration-dependent manner by coexpression with b1 and to a lesser extent with b3. 44 Thus, reduction of VGSCb-expression, and b1 in particular, could be a successful strategy for reducing VGSC activity (and hence metastatic cell behaviour) via several mechanisms.…”

Section: Vgsca and Vgscb Interactions In Cap Cellsmentioning

confidence: 99%

β-Subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression

Diss

Fraser

Walker

et al. 2007

Prostate Cancer Prostatic Dis

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We previously identified high levels of Na v 1.7 voltage-gated sodium channel a-subunit (VGSCa) mRNA and protein in human prostate cancer cells and tissues. Here, we investigated auxillary b-subunit (VGSCbs) expression. In vitro, the combined expression of all four VGSCbs was significantly (B4.5-fold) higher in strongly compared to weakly metastatic cells. This was mainly due to increased b1-expression, which was under androgenic control. In vivo, b1-b4 mRNAs were detectable and their expression in CaP vs non-CaP tissues generally reflected the in vitro levels in relation to metastatic potential. The possible role(s) of VGSCbs (VGSCa-associated and VGSCaindependent) in prostate cancer are discussed.

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Section: Vgsca and Vgscb Interactions In Cap Cellsmentioning

confidence: 99%

β-Subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression

Diss

Fraser

Walker

et al. 2007

Prostate Cancer Prostatic Dis

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“…While investigating whether β-subunits also influence ligand interactions, we found that β4 dramatically alters toxin binding to Na v 1.2. To explore these observations further, we solved the crystal structure of the extracellular β4 domain and identified 58 Cys as an exposed residue that, when mutated, eliminates the influence of β4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of β4.…”

mentioning

confidence: 99%

“…Here, we investigated whether β-subunits influence Na v channel sensitivity to molecules isolated from animal venom and discovered that β4 can drastically alter the response of the neuronal Na v 1.2 isoform to spider and scorpion toxins that target paddle motifs within Na v channel voltage sensors. To elucidate the machinery underlying this observation, we solved the crystal structure of the extracellular β4 domain and found a 58 Cys-containing binding interface that is involved in Na v channel modulation of toxin pharmacology by β4. Remarkably, dismantling the strictly conserved internal cysteine bridge in β4 by introducing a β1 mutation implicated in epilepsy (30) does not preclude protein folding and trafficking to the membrane.…”

mentioning

confidence: 99%

“…Remarkably, dismantling the strictly conserved internal cysteine bridge in β4 by introducing a β1 mutation implicated in epilepsy (30) does not preclude protein folding and trafficking to the membrane. However, conformational changes induced by the mutation perturb the 58 Cys-containing loop and disrupt β4 interaction with Na v 1.2, in turn altering the functional and pharmacological properties of the larger Na v channel signaling complex.…”

mentioning

confidence: 99%

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Crystallographic insights into sodium-channel modulation by the β4 subunit

Gilchrist

Das

Petegem

et al. 2013

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

110

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Voltage-gated sodium (Na v ) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, β-subunits modify Na v channel function and cause debilitating disorders when mutated. While investigating whether β-subunits also influence ligand interactions, we found that β4 dramatically alters toxin binding to Na v 1.2. To explore these observations further, we solved the crystal structure of the extracellular β4 domain and identified 58 Cys as an exposed residue that, when mutated, eliminates the influence of β4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of β4. Disrupting this bridge by introducing a β1 mutation implicated in epilepsy repositions the 58 Cys-containing loop and disrupts β4 modulation of Na v 1.2. Overall, the principles emerging from this work (i) help explain tissuedependent variations in Na v channel pharmacology; (ii) enable the mechanistic interpretation of β-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant β-subunit behavior.voltage-gated sodium channel | beta4 subunit | ProTx-II | X-ray structure | disease mutations

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“…Although it has been reported that blockade of the Na + channel by LAs is differentially modulated by β1 and β3 subunits [20] , this was not of concern in the present study in that we intended to provide a direct assessment of the pharmacological effects of bupivacaine on the Na v 1.5 channel. Hence, Xenopus oocytes were chosen as an expression system of Na v 1.5 alone.…”

Section: Voltage-and Use-dependent Blockade By Bupivacainementioning

confidence: 99%

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

et al. 2014

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Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels (VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Na v 1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacainetriggered arrhythmia. Here, we investigated the effect of bupivacaine on Na v 1.5 within the clinical concentration range. The electrophysiological measurements on Na v 1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltageand concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Na v 1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Na v 1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.

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Lidocaine block of neonatal Nav1.3 is differentially modulated by co-expression of β1 and β3 subunits

Cited by 33 publications

References 40 publications

β-Subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression

β-Subunits of voltage-gated sodium channels in human prostate cancer: quantitative in vitro and in vivo analyses of mRNA expression

Crystallographic insights into sodium-channel modulation by the β4 subunit

Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes

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