Figure 1.

Possible functions of Cx32 in myelinating SCs and topology of Cx32 mutations. (A) Electrical activity of myelinated nerves triggers axonal K⁺ release, whose recycling could involve Cx32 GJs located in SC paranodes and Schmidt–Lanterman incisures. Axonal firing also stimulates ATP release from volume-activated anion channels (VAACs; Fields and Ni, 2010) which induces P2Y-mediated Ca²⁺ increases in the cytosol and the mitochondrial matrix of the surrounding SCs via IP₃ receptors (IP₃R) of the endoplasmic reticulum (ER) and the mitochondrial calcium uniporter (MCU), respectively. The increase in the cytosolic Ca²⁺ concentration ([Ca²⁺]_i) should be sufficient to trigger Cx32 hemichannel opening and ATP release, contributing to the intracellular and intercellular propagation of the Ca²⁺ signal. Interaction between Cx32 hemichannels and mitochondria may play a role in cell bioenergetics as found in liver of Cx32-null mice (Fowler et al., 2013). (B) Cx32 mutations belonging to classes 3-4-5 mentioned in the text are represented as colored circles (black-red-azure, respectively) associated to the correspondent WT amino acid (white circle), where the topology of Cx32 domains is derived from the all-atom model of Cx32 connexon in Carrer et al. (2018).