Abstract
The concept of an intercellular channel that mediates the direct intracellular passage of ions, second messengers, and metabolites between adjacent cells was born from the observations of electrical coupling within cellular excitable and nonexcitable tissues in the 1950s and 1960s. Originally called the “nexus”, the term gap junction was applied to this membrane structure after the observation of 1–2 nm gap between adjacent cell membranes populated with hexameric protein bridges containing a central aqueous pore in 1967. Molecular structural models of the gap junction channel evolved in 1977 and approximately every 20 years since with increasing resolution. The first junction channel current records and the cloning of the connexin subunits occurred in the mid-1980s, ushering in the molecular era of gap junction channel research. This atypical intracellular double membrane channel is now known to be formed by 20 different mammalian connexins with 60 % of them linked to inherited human diseases. Once thought to be a large static channel, gap junction channels exhibit with conductances that vary from 10 to 300 pS with ionic and molecular permeabilities that defy the simple principles of a nonselective large aqueous pore. Their activity is modulated by numerous mechanisms including calcium signaling, intracellular pH, post-translation modifications (PTMs) like protein phosphorylation and acetylation, and a variety of lipophiles. Despite knowledge of the connexin membrane topology and primary amino acid sequences for three decades, precise identification of the molecular pore composition of this unconventional ion channel remains poorly understood. Recent development of a 3.5 Å three-dimensional structure and molecular dynamic simulations have facilitated development of precise hypotheses for the origin of cationic and anionic pore permeability barriers amenable to experimental verification.
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Veenstra, R.D. (2015). Gap Junction Channels: The Electrical Conduit of the Intercellular World. In: Delcour, A.H. (eds) Electrophysiology of Unconventional Channels and Pores. Springer Series in Biophysics, vol 18. Springer, Cham. https://doi.org/10.1007/978-3-319-20149-8_13
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