Tmem168, a protein-coding gene, consists of 697 amino acid residues with some putative transmembrane domains. It has been implicated in multiple biological processes and disease-related pathways. In the nucleus accumbens (NAcc), it is associated with drug-dependence regulation and interacts with osteopontin. It may also be involved in the Wnt/β-catenin pathway in glioblastoma cells [1,4,5].

In mice, overexpression of Tmem168 in the NAcc using an adeno-associated virus vector led to attenuation of methamphetamine-induced hyperlocomotion and place preference, and suppressed methamphetamine-induced extracellular dopamine elevation. Additionally, TMEM168 overexpression enhanced anxiety and caused sensorimotor gating deficit, with these effects reversible by relevant drugs. In a family with Brugada syndrome, a heterozygous 1616G > A substitution (R539Q mutation) in Tmem168 was identified. The mutant Tmem168 in HL-1 cardiomyocytes led to a significant decrease in Na+ current and Nav 1.5 protein expression. Heterozygous Tmem168 1616G > A knock-in mice showed ventricular tachyarrhythmias and conduction disorders upon pharmacological stimulation [1,3,4,2].

In conclusion, Tmem168 plays important roles in drug-dependence-related behaviors, anxiety-related phenotypes, and arrhythmogenesis. Mouse models, especially those with Tmem168 overexpression or mutation, have been crucial in revealing these functions, providing insights into potential therapeutic targets for methamphetamine dependence and Brugada syndrome.