Chapter 5 │ Page 165 Cx proteins are able to come together to form a large diversity of strictly organized assemblies. For instance, six Cx protein monomers oligomerize to form a hemichannel usually referred to as “connexon” (Figure 3a), i.e., a hydrophilic pore that enables the passage of molecules for direct cytoplasm-to-extracellular communication [51,56]. Connexons are normally closed, but when activated, they can release autocrine and paracrine signals, such as nicotinamide adenine dinucleotide (NAD+), glutamate, and adenosine triphosphate (ATP). These signals can a ect cell proliferation and survival [57]. The NT domain of a Cx is critical for holding the connexon open, and the pore diameter can di er depending on the Cx they are composed of. For example, a connexon made up of Cx26 proteins has a pore diameter of ~10 Å, as estimated by molecular dynamics (MD) simulations [58] and ~14 Å by crystallography [59] (Figure 3a). Likewise, a connexon made up of Cx46 or Cx50 proteins has a pore diameter of ~14 Å, as visualized with single-particle cryo-electron microscopy [60]. Once at the plasma membrane, two opposing connexons from adjacent cells can interact with each other to form a GJ channel, facilitating GJIC. Depending on the type of GJIC, various biophysical properties will be impacted [61,62]. The GJIC can be either homomeric, i.e., when they are composed of Cxs within the same class (Figure 3b), or heteromeric, i.e., when they are composed of Cxs from di erent classes (Figure 3c). Thus, GJIC could be classified as (1) homotypic-homomeric, which consists of two identical connexons formed by only one class of Cx; (2) heterotypic-homomeric, which consists of di erent connexons, each one formed of the same class of Cx; (3) heterotypic-heteromeric, which consists of di erent connexons, each one formed with two or more non-symmetric isotypes of Cxs; (4) homotypic-heteromeric, which consists of identical connexons, both similar formed with two or more non-symmetric isotypes of Cxs (Figure 3d).
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