Connexin 36 (Cx36), a neuronal gap junction protein, is essential for retinal signal transmission but may also contribute to neurodegeneration by facilitating the spread of excitotoxic stress signals. This study aimed to examine the degradation pathway of Cx36 under stress conditions relevant to retinal disease. Using immortalized 661W murine photoreceptor cells transfected with GFP-tagged Cx36, we evaluated the effects of lysosomal inhibition (Bafilomycin A1) and excitotoxic stimulation (NMDA). Immunofluorescence revealed intracellular Cx36 accumulation following Bafilomycin and NMDA exposure, accompanied by increased expression of p62/SQSTM1 and PSMA1, suggesting impaired autophagic flux and a potential compensatory involvement of the proteasome. Elevated RAB11A levels suggested recruitment of endosomal recycling pathways. NMDA treatment was associated with increased ubiquitin accumulation, particularly in Cx36-overexpressing cells, indicating enhanced proteostatic stress under excitotoxic conditions. These findings highlight the stress-responsive behavior of Cx36 and suggest that connexin proteostasis may represent a potential target for future investigation in retinal neurodegeneration, including glaucoma and age-related macular degeneration. Immunofluorescence revealed intracellular accumulation of p62 and PSMA1 after Bafilomycin exposure with signal intensities increasing approximately 1.5-2-fold versus controls (n = 3, p < 0.05). These data are consistent with disrupted autophagic flux and suggest proteasome involvement, but do not constitute functional proof.
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