Gja1, encoding Connexin 43 (Cx43), is the primary gap junction protein in mammalian heart ventricles [1,3]. Gap junctions formed by Cx43 are crucial for intercellular communication, facilitating the efficient spread of electrical excitation in cardiac muscle [1]. It also plays roles in various cellular processes like cell-cell contact and is implicated in multiple biological pathways and disease-related processes [1,2,4,5,6]. Genetic models, such as knockout (KO) mouse models, are valuable for studying Gja1's functions.

Gja1-20k, an N-terminal truncated protein isoform of Cx43 generated by internal translation of Gja1 mRNA, is essential for the trafficking of full-length Cx43 hexameric hemichannels to cell-cell contacts [1]. Gja1-20k deficient mice (produced by a M213L substitution in Gja1) suffer from poor electrical coupling between cardiomycytes and arrhythmogenic sudden death 2-4 weeks after birth, highlighting its importance in maintaining normal cardiac electrical rhythm [1]. Additionally, exogenous GJA1-20k expression mimics the effect of ischemic preconditioning in mouse heart and localizes to the mitochondrial outer membrane, inducing a protective form of mitochondrial fission independent of DRP1, preserving ATP production and reducing reactive oxygen species (ROS) under metabolic stress [1].

In conclusion, Gja1 is vital for normal cardiac function, especially in maintaining electrical coupling and rhythm through the function of its isoform Gja1-20k. The study of Gja1-20k deficient mouse models has provided insights into the role of Gja1 in cardiac-related diseases, such as arrhythmias and ischemic-related insults, enhancing our understanding of the underlying mechanisms and potentially guiding the development of new therapeutic strategies.