Abstract
Gap junction channels mediate the direct intercellular passage of small ions as well as larger solutes such as second messengers. A family of proteins called connexins make up the subunits of gap junction channels in chordate animals. Each individual connexin forms channels that exhibit distinct permeability to molecules that influence cellular signaling, such as calcium ions, cyclic nucleotides, or inositol phosphates. In this review, we examine the permeability of connexin channels containing Cx43, Cx46, and Cx50 to signaling molecules and attempt to relate the observed differences in permeability to possible in vivo consequences that were revealed by studies of transgenic animals where these connexin genes have been manipulated. Taken together, these data suggest that differences in the permeability of individual connexin channels to larger solutes like 3′,5′-cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate (IP3) could play a role in regulating epithelial cell division, differentiation, and homeostasis in organs like the ocular lens.
Highlights
Tissues require continuous exchange of information between their constituent cells to coordinate activities required for growth and development
We review the published evidence on differences in second messenger permeability through connexin channels made of Cx43, Cx46, and Cx50 and speculate on how this may contribute to the regulation of the intercellular communication necessary for normal growth of the lens
Differences in cyclic adenosine monophosphate (cAMP) permeability through gap junction channels formed by different connexins have been measured using two different approaches: a quantitative patch clamp assay relying on activation of the cyclic nucleotide-gated channel SpIH in cell pairs [3,36,38,39] or the microscopic observation of the cell-to-cell passage of fluorescent ε-cAMP [36]
Summary
Tissues require continuous exchange of information between their constituent cells to coordinate activities required for growth and development This communication is mediated in part through the activation of intracellular signal transduction by extracellular growth factors to generate second messengers, which can be directly propagated between adjacent cells through the connexin channels present in gap junctions. Genetic studies in mice have suggested that the functional differences observed between connexins in vitro are important in vivo, since the loss of one isoform cannot be compensated for by replacement with another connexin within the same cell type or tissue [7,8,9,10,11] This raises the intriguing prospect that differences in the permeability to second messengers is one possible reason for why so many different connexin genes are required in any given cell type [5]. We review the published evidence on differences in second messenger permeability through connexin channels made of Cx43, Cx46, and Cx50 and speculate on how this may contribute to the regulation of the intercellular communication necessary for normal growth of the lens
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