Matching sodium channel availability to resting membrane potential: Biophysical logic across excitable cell types

Excitable tissues like the brain, peripheral nerves, skeletal muscles and the heart share a common dependence on voltage-gated sodium (Nav) channels for the initiation and propagation of action potentials (APs). These Nav channels exhibit unique biophysical properties tailored to their specific cellular environments. Here, we explore the interactions between Nav channel availability and resting membrane potential across a spectrum of cell types, including inhibitory GABAergic neurons, excitatory glutamatergic neurons, skeletal muscles, cardiomyocytes and dorsal root ganglion neurons. We highlight how these interactions, modulated by post-translational modifications and in relation to spatial localizations, are critical for maintaining physiological function and how even small shifts in channel properties can have significant pathophysiological consequences. In addition, we discuss the implications for drug discovery, emphasizing the need to consider the native cellular environment in developing Nav-targeting therapies. This perspective provides a framework for understanding the nuanced role of Nav channels in health and disease.