Gasotransmitters in the regulation of connexins in central and peripheral nervous system injuries

Gasotransmitters, such as nitric oxide, carbon monoxide, and hydrogen sulfide can freely diffuse across biological membranes, bind to receptors and molecular targets, and modulate multiple intracellular signaling pathways. However, no systematic review exists regarding how gasotransmitters influence central and peripheral nervous system injury by regulating connexins. This review study presents, for the first time, a systematic analysis of the effects of these three gasotransmitters on connexin regulation, with a focus on their potential roles in injuries to the central and peripheral nervous systems. The results of the systematic analysis showed that carbon monoxide can exert both neuroprotective and neurotoxic effects through S-nitrosylation, phosphorylation, and regulation of connexin channels, as well as contribute to neurovascular coupling and ischemic preconditioning. Carbon monoxide primarily modulates connexin activity via the heme oxygenase-1/carbon monoxide/nuclear factor erythroid 2-related factor 2 signaling pathways, demonstrating potential in reducing neuroinflammation and necroptosis. Hydrogen sulfide also affects connexin-related signaling pathways, regulates platelet aggregation and regulatory T cell- mediated immune responses, and supports vascular homeostasis. Importantly, connexins function as molecular hubs integrating gasotransmitter-dependent signals, thereby mediating both secondary injury cascades and neuroregenerative processes. The obtained results indicate that connexins represent promising therapeutic targets, and pharmacological strategies based on gasotransmitters constitute a novel direction in neuroprotection after neural injury. However, the clinical application of these approaches remains limited, and further studies are required to clarify isoform-specific connexin regulation, optimize gasotransmitter delivery systems, and minimize potential systemic toxicity.