The Nax (SCN7A) channel: an atypical regulator of tissue homeostasis and disease

Within an articulately characterized family of ion channels, the voltage-gated sodium channels, exists a black sheep, SCN7A (Na-x). Na-x, in contrast to members of its molecular family, has lost its voltage-gated character and instead rapidly evolved a new function as a concentration-dependent sensor of extracellular sodium ions and subsequent signal transducer. As it deviates fundamentally in function from the rest of its family, and since the bulk of the impressive body of literature elucidating the pathology and biochemistry of voltage-gated sodium channels has been performed in nervous tissue, reports of Na-x expression and function have been sparse. Here, we investigate available reports surrounding expression and potential roles for Na-x activity outside of nervous tissue. With these studies as justification, we propose that Na-x likely acts as an early sensor that detects loss of tissue homeostasis through the pathological accumulation of extracellular sodium and/or through endothelin signaling. Sensation of homeostatic aberration via Na-x then proceeds to induce pathological tissue phenotypes via promotion of pro-inflammatory and pro-fibrotic responses, induced through direct regulation of gene expression or through the generation of secondary signaling molecules, such as lactate, that can operate in an autocrine or paracrine fashion. We hope that our synthesis of much of the literature investigating this understudied protein will inspire more research into Na-x not simply as a biochemical oddity, but also as a potential pathophysiological regulator and therapeutic target.