Connexin 43 hemichannel-mediated ATP release in depression: recent advances and mechanistic insights

Major depressive disorder (MDD) is a severe mental illness that poses a significant threat to human health, with an extremely complex pathogenesis that presents major challenges for traditional treatments. Emerging evidence indicates that energy metabolism disorders, particularly ATP release mediated by connexin 43 (Cx43) hemichannels, play a crucial role in the pathogenesis of MDD and hold potential as therapeutic targets. Cx43 is primarily expressed in astrocytes, where it forms hemichannels (HCs) in the cell membrane to regulate ATP release. Stress-induced abnormal opening of Cx43 hemichannels leads to increased release of ATP into the extracellular space. In the acute phase, ATP released through these channels might activate the P2X7 receptor. Conversely, chronic stress conditions might involve an excessive ATP release from astrocytes together with an ATP depletion, which in might result in neuronal deficits. This imbalanced ATP and adenosine signaling might exacerbate depressive symptoms by disrupting normal neuronal function and synaptic plasticity. ATP metabolites like adenosine also modulate depression through adenosine receptors (A1R, A2AR). This review emphasizes that Cx43-mediated ATP release might be a critical modulator of glial-neuronal communication, and assesses the potential of Cx43 as a therapeutic target.