Figure 20.

The Ca-CaM-Cork gating model proposes that at normal [Ca²⁺]_i (~50 nM) CaM is anchored to each connexin by its C-lobe to the CL2 site (A, white-colored connexins). With a [Ca²⁺]_i rise, one scenario could be that each N-lobe binds to the NT or CL2 site of the same connexin (trans-domain interaction) and change the connexin conformation (B, yellow-colored connexins); this would allow an N-lobe to access the channel’s mouth and plug the pore by binding to the NT or CL2 site of the opposite connexin (B, trans-subunit interaction – “cork gating”). Another scenario could be that with a [Ca²⁺]_i rise all of the N-lobes are activated, but only one binds to a site of the opposite connexin and plugs the pore (C, “cork gating”). If this were the case, the first Ca²⁺-activated N-lobe would win the competition (first come, first served), preventing other N-lobes from accessing the channel’s mouth.