Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation?

Figure 2

Cx43 channel gating by CT-CL interactions and possible effects of Cx43 C-terminal cleavage on hemichannel function. The Cx43 C-terminal domain is intricately involved in gating of both HCs and GJ channels. (a) In normal conditions, GJ channels are open, with the C-terminal domains not interacting with the CLs. GJ closure occurs when the CT binds the CL (ball-and-chain closure). In GJ channels composed of CT-truncated Cx43, closure via the ball-and-chain mechanism cannot occur and GJ channels remain open. (b) An intramolecular CT-CL interaction has been proposed to bring Cx43HCs in the “available to open” state whereas in the absence of such interaction, HCs remain closed. HC closure at above 500 nM is mediated by cytoskeletal contractions that dislocate the C-terminal domain from the CL and act as a brake on HC opening. Such CT-CL interaction cannot take place in HCs consisting of C-terminally truncated Cx43, making them refractive for activation. MMP cleavage of Cx43HCs in the “available to open” state will result in a C-terminal peptide that is bound to the CL. This will cause loss of the high brake when the cleavage site is located downstream of the Cx43-actomyosin interaction site. When the MMP cleavage site is located N-terminally of this actomyosin linker domain, the outcome is less clear. In principle, actomyosin contraction may remove the CT peptide from the CL, but a residual interaction of the CL with more upstream sequences may keep the HC in an “available to open” state. Identification of the actomyosin interaction domain within the Cx43 C-terminal domain responsible for mediating the high brake on HC opening will resolve these uncertainties.

(a) Gap junctions

(b) Hemichannels