NaV1.7 Splice Variant from Human Heart Compared with Neuronal hNaV1.7

Abstract

Perception of noxious stimuli can be profoundly affected by mutations in the gene SCN9A which encodes the α-subunit of the voltage-gated sodium channel NaV1.7. Mutantions of this channel are associated with chronic pain or complete absence of pain. Primary erythermalgia and paroxysmal extreme pain disorder are syndromes associated with attacks of severe pain resulting from mutations that enhance NaV1.7 channel activity. Non-sense mutations in SCN9A lead to complete loss of NaV1.7 function. Loss of NaV1.7 function produces complete insensitivity to pain and anosmia, but little other changes in functions or behaviors. The pain-specific nature of the mutant NaV1.7 phenotypes is in keeping with the notion that this channel is expressed primarily in dorsal root ganglia and, to a lesser extent in the sympathetic ganglia. These premises make NaV1.7 an ideal target for the development of novel non-addictive analgesics. However, expression of NaV1.7 has been detected in the heart, with 5- to 10-fold higher levels in human cardiac Purkinje fibres versus the right atrium and ventricle and bradycardia and cardiac asystole have been reported in patients with paroxysmal extreme pain disorder. While these events have usually been ascribed to autonomic effects of the NaV1.7 mutations, a more direct effect of altered NaV1.7 in the heart cannot be ruled out. We have set out to clone and characterize the specific NaV1.7 subtype expressed in the human heart. In the present study we cloned and characterized a NaV1.7 subtype predominantly expressed in the human heart. This novel splice variant, missing one exon, may impact drug safety for this emerging family of analgesics. Its biophysical and pharmacological properties have been studied and will be discussed in comparison to the neuronal variant.