The noncanonical functions of Cx43 in the heart

Abstract

There is abundant evidence showing that connexins form gap junctions. Yet this does not exclude the possibility that connexins can exert other functions, separate from that of gap junction (or even a permeable hemichannel) formation. Here, we focus on these noncanonical functions of connexin43 (Cx43), particularly in the heart. We describe two specific examples: the importance of Cx43 on intercellular adhesion, and the role of Cx43 in the function of the sodium channel. We propose that these two functions of Cx43 have important repercussions on the propagation of electrical activity in the heart, irrespective of the presence of permeable gap junction channels. Overall, the gap junction-independent functions of Cx43 in cardiac electrophysiology emerge as an exciting area of future research.

Figure 1

Diagram indicating cross-talk between gap junctions, mechanical junctions and ion channel complexes. Gap junctions refers to Cx43 while mechanical junctions includes desmosomes and adherens junctions (N-cadherin). Ion channel complexes refers primarily to sodium channel complex and K_v1.5. Citations correspond to experimental evidence in cardiac preparations that support the interaction described.

Figure 2

Loss of Cx43 induces loss of intercellular adhesion strength. A) Western blot for Cx43 in HEK293 cells untreated (UNT), treated with a virus that contains a non-silencing construct ( shRNA-Cx43) and silenced for Cx43 (shRNA-Cx43). GAPDH was used as loading control. B) Dispase assay. Cells were treated with 2.4U/mL dispase for 90min to disrupt attachment to extracellular matrix. Images were taken before (t₀) and after 5-10 inversion cycles. Bars show number of fragments after subjecting monolayers to 5-10 inversion cycles. n=10-20, p<0.001