Jack Butler, Nicholas Dale

Connexin32 (Cx32) is expressed in myelinating Schwann cells. It forms both reflexive gap junctions, to facilitate transfer of molecules from the outer to the inner myelin layers and hemichannels at the paranode to permit action potential-evoked release of ATP into the extracellular space. Loss of function mutations in Cx32 cause X-linked Charcot Marie Tooth disease (CMTX), a slowly developing peripheral neuropathy. The mechanistic links between Cx32 mutations and CMTX are not well understood. As Cx32 hemichannels can be opened by increases in PCO₂, we have examined whether CMTX mutations alter this CO₂ sensitivity. We have shown that Schwannoma RT4 D6P2T cells can release ATP in response to elevated PCO₂ via the opening of Cx32. This is consistent with the hypothesis that the CO₂ sensitivity of Cx32 may be important for maintenance of healthy myelin. Our data, showing a transdominant effect of certain CMTX mutations on CO₂ sensitivity, may need to be taken into account in any future gene therapies for this condition.

Frontiers in Cellular Neuroscience. December 2023