1.A.24.1.5
Heteromeric (or homomeric) Connexin46/Connexin50 junction (Cx46/Cx50; Cnx46/Cnx50; GJA8/GJA3) protein.  Mutations in CX46 or Cx50 cause cataracts, a cause of visual impairment and blindness (Derosa et al., 2007; Wang and Zhu 2012; Ye et al. 2019), and mutations in Cx46 can cause breast cancer (Grek et al. 2016). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011).  The N-terminal half of connexin 46 appears to contain the core elements of the pore and voltage gates (Kronengold et al. 2012).  In Cx46, neutralization of negative charges or addition of positive charge in the Cx26 equivalent region reduced the slow gate voltage dependence. In Cx50 the addition of a glutamate in the same region decreased the voltage dependence, and the neutralization of a negative charge increased it. Thus, the charges at the end of TMS1 are part of the slow gate voltage sensor in Cxs. The fact that Cx42, which has no charge in this region, still presents voltage dependent slow gating, suggests that charges still unidentified also contribute to the slow gate voltage sensitivity (Pinto et al. 2016).  Cx43 is regulated by phosphorylation of Ser-373 (Puebla et al. 2016). A connexin50 mutation in the heterozygous state affects the lipid profile and the oxidative stress parameters in a spontaneously hypertensive rat strain (Šeda et al. 2016). Mutations in Cx50 (N220D and V44M) are responsible for congenital cataracts (Kuo et al. 2017; Zhang et al. 2018) Mutations its gene cause defects in early eye development (Ceroni et al. 2019). Cx50 is important for eye lens transparency, and calmoduin and Ca²⁺ cooperate in the gating control of Cx50 hemichannels (Zhang et al. 2006). Cx46 hemichannels are modulated by nitric oxide, and the fourth TMS cysteine may be involved in cataract formation (Retamal et al. 2019).  Gap19 is a Cx43 hemichannel inhibitor that acts as a gating modifier that decreases main state opening while increasing substate gating (Lissoni et al. 2020). Cx46, almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and correlates with tumor growth (Acuña et al. 2020). EphA2 is required for normal Cx50 localization to the cell membrane, and conductance of lens fiber cells requires normal Eph-ephrin signaling and water channel (Aqp0) localization (Cheng et al. 2021). The Gja8 (Cx50) mutation gives rise to a cataract rat model (Shen et al. 2023). The V219F mutation in Gja8, induced semi-dominant nuclear cataracts. The p.V219F mutation altered Cx50 distribution, inhibited lens epithelial cell proliferation, migration, and adhesion, and disrupted fiber cell differentiation. As a consequence, the nuclear cataract and small lens formed (Shen et al. 2023). León-Fuentes et al. 2023 have reviewed the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells. Bioelectrical signal propagation involving Cx46 within the developing neuromuscular system is required for appropriate myofiber organization, and disruption leads to defects in behavior (Lukowicz-Bedford et al. 2023).