Slc6a2, also known as the gene encoding the noradrenaline (norepinephrine) transporter (NET), plays a pivotal role in regulating neurotransmitter balance. It terminates noradrenergic transmission by reuptaking noradrenaline into presynaptic neurons, utilizing sodium and chloride gradients. This process is crucial for normal physiology and neurobiology, and the gene is a pharmacological target for antidepressants and analgesic drugs [1,5,6].

Genetic deletion of Slc6a2 in sympathetic neuron-associated macrophages (SAMs) in mouse models reveals its importance in obesity-related mechanisms. Without Slc6a2, SAMs can no longer effectively clear norepinephrine, leading to increased brown adipose tissue content, browning of white fat, enhanced thermogenesis, and significant weight loss in obese mice. This indicates that Slc6a2 in SAMs is involved in the regulation of thermogenesis and obesity [3]. In addition, studies on genetic variants of Slc6a2 in humans show associations with various conditions. For example, in ASD children comorbid with ADHD treated with methylphenidate, certain Slc6a2 haplotype combinations are associated with somnolence. In Han Chinese MDD patients treated with venlafaxine, specific Slc6a2 variants are related to treatment remission. Also, in ADHD patients treated with atomoxetine, all six studied Slc6a2 polymorphisms are associated with treatment response [2,4,7].

In conclusion, Slc6a2 is essential for noradrenergic neurotransmission regulation. Mouse models with Slc6a2 gene knockout in specific cell types have illuminated its role in obesity-related thermogenesis regulation. In humans, its genetic variants are associated with the treatment response of drugs for neuropsychiatric disorders like ADHD and MDD, highlighting its significance in understanding disease mechanisms and personalized medicine.

References:

1. Zhang, Heng, Yin, Yu-Ling, Dai, Antao, Xu, H Eric, Jiang, Yi. 2024. Dimerization and antidepressant recognition at noradrenaline transporter. In Nature, 630, 247-254. doi:10.1038/s41586-024-07437-6. https://pubmed.ncbi.nlm.nih.gov/38750358/

2. Hernandez, Marta H, Bote, Valentin, Serra-LLovich, Alexandre, Hervas, Amaia, Arranz, Maria J. 2022. CES1 and SLC6A2 Genetic Variants As Predictors of Response To Methylphenidate in Autism Spectrum Disorders. In Pharmacogenomics and personalized medicine, 15, 951-957. doi:10.2147/PGPM.S377210. https://pubmed.ncbi.nlm.nih.gov/36393977/

3. Pirzgalska, Roksana M, Seixas, Elsa, Seidman, Jason S, Glass, Christopher K, Domingos, Ana I. 2017. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. In Nature medicine, 23, 1309-1318. doi:10.1038/nm.4422. https://pubmed.ncbi.nlm.nih.gov/29035364/

4. Yeh, Yi-Wei, Chen, Cheng-Jueng, Jang, Fong-Lin, Lu, Ru-Band, Huang, San-Yuan. 2014. SLC6A2 variants may predict remission from major depression after venlafaxine treatment in Han Chinese population. In Journal of psychiatric research, 61, 33-9. doi:10.1016/j.jpsychires.2014.11.017. https://pubmed.ncbi.nlm.nih.gov/25512257/

5. Hu, Tuo, Yu, Zhuoya, Zhao, Jun, Loland, Claus J, Zhao, Yan. 2024. Transport and inhibition mechanisms of the human noradrenaline transporter. In Nature, 632, 930-937. doi:10.1038/s41586-024-07638-z. https://pubmed.ncbi.nlm.nih.gov/39085602/

6. Tan, Jiaxin, Xiao, Yuan, Kong, Fang, Yuan, Yafei, Yan, Chuangye. 2024. Molecular basis of human noradrenaline transporter reuptake and inhibition. In Nature, 632, 921-929. doi:10.1038/s41586-024-07719-z. https://pubmed.ncbi.nlm.nih.gov/39048818/

7. Kole, Ismail Hasan, Vural, Pınar, Yurdacan, Beste, Alemdar, Adem, Mutlu, Caner. 2024. Evaluation of SLC6A2 and CYP2D6 polymorphisms' effects on atomoxetine treatment in attention deficit and hyperactivity disorder. In European journal of clinical pharmacology, 80, 1773-1785. doi:10.1007/s00228-024-03744-z. https://pubmed.ncbi.nlm.nih.gov/39158690/