Cardiac Cx43, Cx40 and Cx45 co-assembling: involvement of connexins epitopes in formation of hemichannels and Gap junction channels

Abstract

Background: This review comes after the International Gap Junction Conference (IGJC 2015) and describes the current knowledge on the function of the specific motifs of connexins in the regulation of the formation of gap junction channels. Moreover the review is complemented by a summarized description of the distinct contribution of gap junction channels in the electrical coupling.

Results: Complementary biochemical and functional characterization on cell models and primary cells have improved our understanding on the oligomerization of connexins and the formation and the electrical properties of gap junction channels. Studies mostly focused cardiac connexins Cx43 and Cx40 expressed in myocytes, while Cx45 and Cx30.2 have been less investigated, for which main findings are reviewed to highlight their critical contribution in the formation of gap junction channels for ensuring the orchestrated electrical impulse propagation and coordination of atrial and ventricular contraction and heart function, whereas connexin dysfunction and remodeling are pro-arrhythmic factors. Common and specific motifs of residues identified in different domain of each type of connexin determine the connexin homo- and hetero-oligomerization and the channels formation, which leads to specific electrical properties.

Conclusions: These motifs and the resulting formation of gap junction channels are keys to ensure the tissue homeostasis and function in each connexin expression pattern in various tissues of multicellular organisms. Altogether, the findings to date have significantly improved our understanding on the function of the different connexin expression patterns in healthy and diseased tissues, and promise further investigations on the contribution in the different types of connexin.

Fig. 1

cardiac Cxs patterns of expression. Note the ubiquitous co-expression of 2, 3 and 4 Cxs isoforms. (The abbreviated anatomical regions are defined at the beginning of the manuscript). (modified from Severs et al, 2008)

Fig. 2

connexin composition of connexons and GJCs in cells co-expressing 2 and 3 Cxs isoforms. a: homomeric connexons: double Cxs co-expression (left panel) and triple Cxs co-expression (right panel). b: examples of diverse Cxs compositions of heteromeric connexons made of 2 isoforms: double Cxs co- expression (left panel) and triple Cxs co-expression (right panel). c: examples of diverse Cxs compositions of heteromeric connexons made of 3 isoforms. The colored numbers indicate the relative amount of Cxs isoforms. d: diverse types of GJCs for a triple Cxs co-expression: homotypic (left panel), heterotypic (middle panel), and heteromeric (right panel). The numbers in frames indicate the statistical total amount of each configuration

Fig. 3

Triplets of Cys identified in the EL1 and EL2 domains of mCx30.2. Note that illustrates the high conservation of this motif between the 4 cardiac Cxs. The sequence alignment with Cx43 has been made with MAFFT software