Decoding Connexin Hemichannels: Structure, Function, and Regulatory Mechanisms

Connexin hemichannels are pivotal for cellular communication, acting as independent conduits for ion and metabolite exchange, as well as precursors to gap junction channels. While their involvement in pathophysiological conditions, including cardiovascular, neurodegenerative, and inflammatory diseases, is well-documented, their physiological roles in tissue homeostasis and cellular signaling remain under active investigation. Despite considerable progress, our understanding of the mechanisms governing hemichannel gating, permeation, structural dynamics, and regulation remains incomplete. This review summarizes key foundational insights into recent advancements to offer a comprehensive perspective on hemichannel function. We explore the molecular determinants of hemichannel opening and closing, their interactions with cellular signaling networks, and structural adaptations that modulate permeation and gating. By integrating these findings, we highlight emerging concepts in connexin hemichannel regulation and underscore their potential as novel therapeutic targets in a variety of disease contexts.