Interactions of Local Anesthetics with Voltage-gated Na+ Channels

Nau, Carla; Wang, G.K.

doi:10.1007/s00232-004-0702-y

Cited by 169 publications

(147 citation statements)

References 69 publications

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“…This is in line with the well studied open channel block caused PAs on inward rectifying K ϩ channels (17,42) and Ca 2ϩ -permeable AMPA channels (29,31). As noted above, activity-dependent block explains the preferential action of PA on I NaP and the repetitive late channel openings that underlie it (43). It is noteworthy that the changes illustrated in Fig.…”

Section: Discussionsupporting

confidence: 87%

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Fleidervish

Libman

Katz

et al. 2008

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

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Because the excitable properties of neurons in the neocortex depend on the characteristics of voltage-gated Na ؉ channels, factors which regulate those characteristics can fundamentally modify the dynamics of cortical circuits. Here, we report on a novel neuromodulatory mechanism that links the availability of Na ؉ channels to metabolism of polyamines (PAs) in the cerebral cortex. Using single channel and whole-cell recordings, we found that products of PA metabolism, the ubiquitous aliphatic polycations spermine and spermidine, are endogenous blockers of Na ؉ channels in layer 5 pyramidal cells. Because the blockade is activity-dependent, it is particularly effective against Na ؉ channels which fail to inactivate rapidly and thus underlie the persistent Na ؉ current. At the level of the local cortical circuit, pharmacological depletion of PAs led to increased spontaneous spiking and periods of hypersynchronous discharge. Our data suggest that changes in PA levels, whether associated with normal brain states or pathological conditions, profoundly modify Na ؉ channel availability and thereby shape the integrative behavior of single neurons and neocortical circuits.neocortex ͉ Layer 5 pyramidal neuron ͉ persistent sodium current ͉ sodium channel ͉ spermine

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Section: Discussionsupporting

confidence: 87%

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Fleidervish

Libman

Katz

et al. 2008

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

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“…Among these mutant channels are WCW-F1579A, WCW-F1579K, WCW-L1280K, and WCW-N434K. These specific residues in rNav1.4 channels (F1579, L1280, and N434) are located in the middle of S6 segments and appear critical for local anesthetic binding (Nau and Wang, 2004). For transient transfection HEK293t cells were grown to ~50% confluence in DMEM (Life Technologies, Inc., Rockville, MD) containing 10% fetal bovine serum (HyClone, Logan, UT), 1% penicillin and streptomycin solution (Sigma, St. Louis, MO), 3 mM taurine, and 25 mM HEPES (Life Technologies, Inc.) and transfected by calcium phosphate precipitation.…”

Section: Transient Transfection Of Hek293t Cells With S6 Mutants In Tmentioning

confidence: 99%

“…Four S6 mutants were created in WCW background: F1579K, F1579A, L1280K, and N434K. These mutants affect local anesthetic binding significantly, particularly on the open-channel block (Nau and Wang, 2004). Fig.…”

Section: Capsaicin Blocks Na + Currents Via a Receptor That Is Distinmentioning

confidence: 99%

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

Wang

Mitchell

Wang

2007

Pain

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Capsaicin elicits burning pain via the activation of the vanilloid receptor (TRPV1). Intriguingly, several reports showed that capsaicin also inhibits Na + currents but the mechanisms remain unclear. To explore this non-TRPV1 action we applied capsaicin to HEK293 cells stably expressing inactivation-deficient rat skeletal muscle Na + mutant channels (rNav1.4-WCW). Capsaicin elicited a conspicuous time-dependent block of inactivation-deficient Na + currents. The 50% inhibitory concentration (IC 50 ) of capsaicin for open Na + channels at +30 mV was measured 6.8 ± 0.6 μM (n = 5), a value that is 10-30 times lower than those for resting (218 μM) and inactivated (74 μM) wildtype Na + channels. On-rate and off-rate constants for capsaicin open-channel block at +30 mV were estimated to be 6.37 μM −1 s −1 and 34.4 s −1 , respectively, with a calculated dissociation constant (K D ) of 5.4 μM. Capsaicin at 30 μM produced ~70% additional use-dependent block of remaining rNav1.4-WCW Na + currents during repetitive pulses at 1 Hz. Site-directed mutagenesis showed that the local anesthetic receptor was not responsible for the capsaicin block of the inactivation-deficient Na + channel. Interestingly, capsaicin elicited little time-dependent block of batrachotoxin-modified rNav1.4-WCW Na + currents, indicating that batrachotoxin prevents capsaicin binding. Finally, neuronal open Na + channels endogenously expressed in GH 3 cells were as sensitive to capsaicin block as rNav1.4 counterparts. We conclude that capsaicin preferentially blocks persistent late Na + currents, probably via a receptor that overlaps the batrachotoxin receptor but not the local anesthetic receptor. Drugs that target such a non-TRPV1 receptor could be beneficial for patients with neuropathic pain.

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“…O sítio de fosforilação é uma serina, altamente conservada, na alça entre os domínios III e IV; a fosforilação pela proteína quinase C reduz a condutância máxima do canal e altera sua ativação. [72][73][74][82][83][84][85][86][87][88] A Tabela 3 resume as informações acima, apresentando regiões específicas relacionadas a diferentes funções ou à regulação do canal de sódio voltagem-dependente.…”

Section: Estrutura Do Canal De Sódio Voltagemdependenteunclassified

Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente

Araújo¹,

Paula²,

Fraceto³

2008

Quím. Nova

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Recebido em 28/11/06; aceito em 30/11/07; publicado na web em 11/9/08 LOCAL ANESTHETICS: INTERACTION WITH BIOLOGICAL MEMBRANES AND WITH THE VOLTAGE-GATED SODIUM CHANNEL. Many theories about the mechanism of action of local anesthetics (LA) are described in the literature. Two types of theories can be distinguished: those that focus on the direct effects of LA on their target protein in the axon membranes, i.e. the voltage-gated sodium channel and the ones that take into account the interaction of anesthetic molecules with the lipid membrane phase for the reversible nerve blockage. Since there is a direct correlation between LA hydrophobicity and potency, it is crucial to take this physico-chemical property into account to understand the mechanism of action of LA, be it on the sodium channel protein, lipid(s), or on the whole membrane phase.Keywords: local anesthetic; membrane; voltage-gated sodium channel. introdUçãoAnestésicos locais (AL) compreendem um grande número de moléculas, de diferentes estruturas químicas, como amino-ésteres, amino-amidas, amino-cetonas, amidas, álcoois, tio-ésteres, tioamidas, derivados de uréia, poliéteres, 1 derivados de monoterpenos do carano 2 etc, capazes de bloquear reversivelmente a condução do estímulo nervoso.As ações estimulatórias e euforizantes da cocaína, presente em grandes quantidades nas folhas de Erythroxylon coca, são conhecidas há séculos pelos povos andinos. Mas foi somente em 1860 que a cocaína foi isolada pela primeira vez por Albert Niemann, que constatou que a mesma causava entorpecimento da língua. As propriedades anestésicas da cocaína levaram à sua classificação como o primeiro anestésico de ação local. Em 1884, Carl Koller introduziu a cocaína na prática clínica como um anestésico para cirurgia oftalmológica 3 e até o início do século XX era possível encontrar produtos cujo princípio ativo era a cocaína (Figura 1). Experiências posteriores, realizadas por Sigmund Freud e outros, demonstraram o grande potencial para desenvolvimento de dependência química, o que levou à proibição do uso da cocaína em 1914.Diferentes AL utilizados atualmente na clínica originam-se dessas primeiras observações clínicas.4,5 A tentativa de diminuir o potencial tóxico da cocaína levou ao desenvolvimento de análogos sintéticos e, em 1890, sintetizou-se a benzocaína, um éster derivado do ácido benzóico, assim como a cocaína. Mas foi em 1904 que apareceu o primeiro AL sintético com potencial uso infiltrativo, a procaína, que se tornou o protótipo dos AL durante quase meio século.6 Outros derivados do ácido para-amino benzóico, como a procaína, foram sintetizados depois e mostraram-se mais potentes (tetracaína) e menos tóxicos (clorprocaína) que a mesma (Tabela 1).A toxicidade de metabólitos do ácido para-amino benzóico 7 e a rápida metabolização da ligação éster por esterases plasmáticas limitavam o uso dos amino-ésteres, o que impulsionou a busca de novos compostos com atividade anestésica, levando à síntese dos AL tipo amino-amida, a partir de 1943 (Tabela 1), os quais atualmente s...

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Interactions of Local Anesthetics with Voltage-gated Na+ Channels

Cited by 169 publications

References 69 publications

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente

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Interactions of Local Anesthetics with Voltage-gated Na+ Channels

Cited by 169 publications

References 69 publications

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na + channels

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na + channels

Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

Anestésicos locais: interação com membranas biológicas e com o canal de sódio voltagem-dependente

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Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na ⁺ channels