Involvement of Na_x sodium channel in peripheral nerve regeneration via lactate signaling

Na_x, a sodium concentration-sensitive sodium channel, is expressed in non-myelinating Schwann cells of the adult peripheral nervous system, but the pathophysiological role remains unclear. We found that functional recovery of the hind paw responses from the sciatic nerve transection was delayed in Na_x knockout (Nax-/- ) mice. Histological analyses showed a decrease in the number of regenerated myelinated axons in Nax-/- sciatic nerves. The delay in the recovery in Nax-/- mice was improved by lactate and inhibited by a monocarboxylate transporter inhibitor. In vitro experiments using cultured Schwann cells showed that lactate release was enhanced by endothelin (ET)-1 and blocked by an ET receptor type B antagonist. Here, it is conceivable that Na_x was activated by ET-1. The amount of lactate release by ET-1 was lower in Nax-/- mice than in wild-type mice. These results indicated that Na_x is functionally coupled to ET for lactate release via ET receptor type B and is involved in peripheral nerve regeneration. Na_x, a sodium concentration-sensitive sodium channel, is expressed in non-myelinating Schwann cells of adult peripheral nervous system. We found that functional recovery of the hind paw responses from the sciatic nerve transection was delayed in Na_x-knockout (Nax-/-) mice. The present study demonstrates that Na_x is functionally coupled to endothelin for lactate release via endothelin receptor type B and involved in peripheral nerve regeneration.