TTXinsensitive

TTXinsensitive is a term used to describe voltage-gated sodium channels that are resistant to inhibition by tetrodotoxin (TTX). While many fast sodium channels are blocked by nanomolar concentrations of TTX, a subset remains functional in its presence, and these are described as TTX-insensitive or TTX-resistant. The best-characterized examples in mammals include Nav1.5 (encoded by SCN5A) in cardiac muscle, and Nav1.8 (SCN10A) and Nav1.9 (SCN11A) in peripheral nociceptive neurons.

Biophysically, TTX binds with high affinity to the outer pore of most sodium channels, blocking sodium permeation. TTX-insensitive channels have alterations in the outer vestibule or selectivity filter that reduce TTX binding, allowing current flow despite TTX.

Physiologically, Nav1.5 mediates the fast upstroke of cardiac action potentials, supporting heart rhythm and conduction. Nav1.8 and Nav1.9 contribute to action potential generation and propagation in certain peripheral neurons involved in pain signaling, where they can operate when TTX-sensitive currents are inhibited.

Clinical and research relevance exists because the differential sensitivity to TTX enables selective pharmacological discrimination of channel subtypes in experiments. Mutations or dysfunction of TTX-insensitive channels, particularly Nav1.5, are linked to cardiac conduction disorders and arrhythmias, while Nav1.8 and Nav1.9 are areas of interest in the study of inflammatory and neuropathic pain. Evolutionarily, TTX insensitivity can reflect adaptations to organisms that encounter TTX, reducing susceptibility to its effects.