Sodium channels are integral membrane proteins that form ion channels and conduct sodium ions (Na+) through the plasma membrane of the cell. In excitable cells such as neurons, muscle cells, and certain types of glial, sodium channels are responsible for the rising phase of action potentials. Importantly, the selective penetration of sodium ions through voltage-dependent sodium channels is the basis for generating action potentials in excitable cells (such as neurons). Besides, voltage-gated sodium channels play an important role in the initiation and propagation of action potentials in neurons and other electrically excited cells.

Moreover, sodium ions flow in through the intact membrane protein that constitutes the channel. It further depolarizes the membrane and initiates the rising phase of the action potential. Furthermore, the Na v channel is the molecular target of a variety of natural neurotoxins. Sodium channels are essential for nerve conduction, skeletal and cardiac muscle contraction, secretion, neurotransmission, and many other processes. Meanwhile, Sodium channels mediate rapid depolarization and conduct electrical impulses throughout the nerves, muscles, and heart. There are three main states of the Nav channel: a closed static state, an open conductive state, and a non-conductive inactive state. Today, we will introduce a membrane-impermeable permanently charged sodium channel blocker, QX-314.

QX-314 is a Membrane-Impermeable Permanently Charged Sodium Channel Blocker.

First of all, QX-314 exerts biphasic effects on transient receptor potential vanilloid subtype 1 channels (TRPV1) in vitro. Nonetheless, QX-314 is a quaternary derivative of lidocaine. QX-314 with 1-60 mM directly activates TRPV1 in a concentration-dependent manner. Particularly, QX-314 exhibits both a frequency- and a voltage-dependent block of Na channels.

In the second place, QX-314 with 10 mM inhibits calcium currents in hippocampal CA1 pyramidal neurons intracellularly. Obviously, the low-threshold (T-type) Ca²⁺ currents are on average < 45% of control amplitude.

Last but not the least, QX-314 directly activates and penetrates human isoforms of TRPV1 and TRPA1 to induce inhibition of sodium channels. In particular, QX-314 has TRPV1 dependent cytotoxicity.

All in all, QX-314 is a membrane-impermeable permanently charged sodium channel blocker.

References:

Talbot MJ, et al. J Neurophysiol. 1996 Sep;76(3):2120-4.