Regulatory role of voltage-gated Na+ channel beta subunits in sensory neurons

Voltage-gated sodium Na+ channels are membrane-bound proteins incorporating aqueous conduction pores that are highly selective for sodium Na+ ions. The opening of these channels results in the rapid influx of Na+ ions that depolarize the cell and drive the rapid upstroke of nerve and muscle action potentials. While the concept of a Na+-selective ion channel had been formulated in the 1940s, it was not until the 1980s that the biochemical properties of the 260-kDa and 36-kDa auxiliary beta subunits (beta 1, beta 2) were first described. Subsequent cloning and heterologous expression studies revealed that the a subunit forms the core of the channel and is responsible for both voltage-dependent gating and ionic selectivity. To date, 10 isoforms of the Na+ channel alpha subunit have been identified that vary in their primary structures, tissue distribution, biophysical properties, and sensitivity to neurotoxins. Four beta subunits (beta 1-beta 4) and two splice variants (beta A, beta B) have been identified that modulate the subcellular distribution, cell surface expression, and functional properties of the a subunits. The purpose of this review is to provide a broad overview of beta subunit expression and function in peripheral sensory neurons and examine their contributions to neuropathic pain.