Role of the cation-chloride-cotransporters in the circadian system

Shihan Salihu; Nur Farah Meor Azlan; Sunday Solomon Josiah; Zhijuan Wu; Yun Wang; Jinwei Zhang

doi:10.1016/j.ajps.2020.10.003

Role of the cation-chloride-cotransporters in the circadian system

Asian J Pharm Sci. 2021 Sep;16(5):589-597. doi: 10.1016/j.ajps.2020.10.003. Epub 2020 Dec 7.

Authors

Shihan Salihu¹, Nur Farah Meor Azlan¹, Sunday Solomon Josiah¹, Zhijuan Wu¹, Yun Wang², Jinwei Zhang¹

Affiliations

¹ Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter EX4 4PS, UK.
² Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Abstract

The circadian system plays an immense role in controlling physiological processes in our body. The suprachiasmatic nucleus (SCN) supervises this system, regulating and harmonising the circadian rhythms in our body. Most neurons present in the SCN are GABAergic neurons. Although GABA is considered the main inhibitory neurotransmitter of the CNS, recent studies have shown that excitatory responses were recorded in this area. These responses are enabled by an increase in intracellular chloride ions [Cl^-]_i levels. The chloride (Cl^-) levels in GABAergic neurons are controlled by two solute carrier 12 (SLC12) cation-chloride-cotransporters (CCCs): Na⁺/K⁺/Cl^- co-transporter (NKCC1) and K⁺/Cl^- co-transporter (KCC2), that respectively cause an influx and efflux of Cl^-. Recent works have found altered expression and/or activity of either of these co-transporters in SCN neurons and have been associated with circadian rhythms. In this review, we summarize and discuss the role of CCCs in circadian rhythms, and highlight these recent advances which attest to CCC's growing potential as strong research and therapeutic targets.

Keywords: Circadian rhythms; GABAergic; K+-2Cl− cotransporter 2 (KCC2); Na+-K+-2Cl− cotransporter 1 (NKCC1); Suprachiasmatic nucleus (SCN); WNK3-SPAK/OSR1, Chloride (Cl−) homoostasis;.

Publication types

Review