Structure, function and pharmacology of voltage-gated sodium channels

Abstract

Voltage-gated sodium channels (VGSCs) are responsible for the initial inwards current during the depolarisation phase of action potential in excitable cells. Therefore, VGSCs are crucial for cardiac and nerve function, since the action potential of nerves and muscle cannot occur without them. Their importance in generation and transmission of signals has been known for more than 40 years but the more recent introduction of new electrophysiological methods and application of molecular biology techniques has led to an explosion of research on many different ion channels, including VGSCs. Their extraordinary biological importance makes them logical and obvious targets for toxins produced by animals and plants for attack or defence. The action of these and similar substances modulating the function of the VGSCs is interesting with respect to their possible use in medicine or use as tools in the study of these molecules. This review summarises recent progress in this research field and, in particular, considers what is known about the relationship of the structure to function, including a current understanding of the pharmacological modulation of VGSCs.

Mechanism of the persistent sodium current activator veratridine‐evoked Ca2+ elevation: implication for epilepsy

“…We analyzed the membrane potential, the [Na + ] i and the [Ca 2+ ] i under the same experimental conditions. We evoked persistent Na + influx by veratridine, which inhibits VGSC inactivation (Denac et al 2000;Ulbricht 2005). Veratridine activates the TTX-sensitive I Na,P (Ulbricht 1965(Ulbricht , 2005Alkadhi and Tian 1996), which may play an initiating role in certain forms of epilepsy (both in VGSC mutants and genetically normal animals; Stafstrom 2007).…”

“…Activation of the persistent Na + current is also known as a cellular mechanism underlying certain epileptic phenotypes (Denac et al 2000;Meisler and Kearney 2005;Stafstrom 2007). Its induction in brain slices by veratridine is used as an epileptic model (Tian et al 1995;Otoom et al 1998).…”

“…Describing the magnitude, temporal pattern and sources of Ca 2+ increase induced by I Na,P may provide novel targets for antiepileptic drug therapy. clonic seizures in humans (Denac et al 2000;Stafstrom 2007) and in in vitro and in vivo models of ischemia (Taylor and Meldrum 1995).…”

“…Veratridine, by binding to the neurotoxin receptor site 2 of VGSCs, inhibits VGSC inactivation and shifts the channel activation threshold toward a more negative membrane potential (Denac et al 2000;Ulbricht 2005). Binding site 2 is also the target of some antiepileptic drugs such as carbamazepine and phenytoin (Willow and Catterall 1982;Worley and Baraban 1987), which also show neuroprotective action (Taylor and Meldrum 1995).…”

A peçonha do escorpião Tityus serrulatus é reconhecida por receptores de reconhecimento padrão e induz ativação celular e inflamação

“…É uma neurotoxina que atua em canais para Na + (CESTELE & CATTERALL, 2000;DENAC et al, 2000), contém 62 aminoácidos (Uniprot ID P68410), incluindo 8 resíduos de cisteína (MANSUELLE et al, 1992) e possui peso molecular de 6.998.…”