Fxyd2, also known as the γ subunit of Na,K-ATPase, is a regulatory subunit that adapts the functional properties of Na,K-ATPase to cellular requirements. Na,K-ATPase is crucial for multiple cellular functions such as maintaining the resting membrane potential, controlling cellular volume, neuronal excitability, and secondary ionic transport [1,4,5]. Fxyd2 is involved in various pathways related to ion transport and neural excitability, and is of great biological importance in processes like renal ion handling and pain sensation [1,2,3,4]. Genetic models, especially knockout (KO) mouse models, have been valuable in studying Fxyd2's functions.

In Fxyd2 -/- mice, there was elevated activity for Na,K-ATPase and for NCC and NKCC2 apical sodium transporters in the kidney, yet the mice were in sodium balance and normotensive. These mice also showed a mild pancreatic phenotype with enhanced glucose tolerance, elevation of circulating insulin, but no insulin resistance, along with an increase in beta cell proliferation and beta cell mass correlated with activation of the PI3K-Akt pathway [7]. In neuropathic pain models, loss of Fxyd2 function, either constitutively in Fxyd2 -/- mice or acutely in neuropathic rats, efficiently alleviated mechanical hypersensitivity induced by peripheral nerve lesions, suggesting its role in maintaining neuropathic pain [3].

In conclusion, Fxyd2 plays essential roles in regulating Na,K-ATPase activity, which in turn impacts multiple biological processes. The study of Fxyd2 KO mouse models has revealed its significance in renal function, pancreatic function, and neuropathic pain. Understanding Fxyd2's functions provides insights into the mechanisms underlying related physiological and pathological conditions, potentially leading to new therapeutic strategies for diseases such as hypomagnesemia, chronic pain, and metabolic disorders [1,2,3,6,7].

References:

1. Mayan, Haim, Farfel, Zvi, Karlish, Steven J D. . Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase. In Physiological reports, 6, e13843. doi:10.14814/phy2.13843. https://pubmed.ncbi.nlm.nih.gov/30175537/

2. Derre, Alexandre, Soler, Noelian, Billoux, Valentine, Pattyn, Alexandre, Venteo, Stephanie. 2023. FXYD2 antisense oligonucleotide provides an efficient approach for long-lasting relief of chronic peripheral pain. In JCI insight, 8, . doi:10.1172/jci.insight.161246. https://pubmed.ncbi.nlm.nih.gov/37154155/

3. Ventéo, Stéphanie, Laffray, Sophie, Wetzel, Christiane, Carroll, Patrick, Pattyn, Alexandre. 2016. Fxyd2 regulates Aδ- and C-fiber mechanosensitivity and is required for the maintenance of neuropathic pain. In Scientific reports, 6, 36407. doi:10.1038/srep36407. https://pubmed.ncbi.nlm.nih.gov/27805035/

4. Wang, Feng, Cai, Bing, Li, Kai-Cheng, Bao, Lan, Zhang, Xu. 2015. FXYD2, a γ subunit of Na⁺, K⁺-ATPase, maintains persistent mechanical allodynia induced by inflammation. In Cell research, 25, 318-34. doi:10.1038/cr.2015.12. https://pubmed.ncbi.nlm.nih.gov/25633594/

5. Cordeiro, Bárbara Martins, Leite Fontes, Carlos Frederico, Meyer-Fernandes, José Roberto. 2024. Molecular Basis of Na, K-ATPase Regulation of Diseases: Hormone and FXYD2 Interactions. In International journal of molecular sciences, 25, . doi:10.3390/ijms252413398. https://pubmed.ncbi.nlm.nih.gov/39769162/

6. de Baaij, Jeroen H F, Dorresteijn, Eiske M, Hennekam, Eric A M, Devuyst, Olivier, Knoers, Nine V A M. 2015. Recurrent FXYD2 p.Gly41Arg mutation in patients with isolated dominant hypomagnesaemia. In Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 30, 952-7. doi:10.1093/ndt/gfv014. https://pubmed.ncbi.nlm.nih.gov/25765846/

7. Arystarkhova, Elena. 2016. Beneficial Renal and Pancreatic Phenotypes in a Mouse Deficient in FXYD2 Regulatory Subunit of Na,K-ATPase. In Frontiers in physiology, 7, 88. doi:10.3389/fphys.2016.00088. https://pubmed.ncbi.nlm.nih.gov/27014088/