Dysfunctional K+ Homeostasis as a Driver

Dysfunctional K⁺ Homeostasis as a Driver: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Neurosciences

Contributor:

The central nervous system (CNS) relies on precise regulation of potassium ion (K⁺) concentrations to maintain physiology. This regulation involves complex cellular and molecular mechanisms that work in concert to regulate both intracellular and extracellular K⁺ levels. Inflammation, a key physiological response, encompasses a series of cell-specific events leading to inflammasome activation. Perturbations in K⁺-sensitive processes can result in either chronic or uncontrolled inflammation, highlighting the intricate relationship between K⁺ homeostasis and inflammatory signalling. This review explores molecular targets that influence K⁺ homeostasis and have been implicated in inflammatory cascades, offering potential therapeutic avenues for managing inflammation. We examine both cell-specific and common molecular targets across different cell types, providing a comprehensive overview of the interplay between K⁺ regulation and inflammation in the CNS. By elucidating these mechanisms, we identify leads for drug discovery programmes aimed at modulating inflammatory responses. Additionally, we highlight potential consequences of targeting individual molecular entities for therapeutic purposes, emphasizing the need for a nuanced approach in developing anti-inflammatory strategies. This review considers current knowledge on K⁺-sensitive inflammatory processes within the CNS, offering critical insights into the molecular underpinnings of inflammation and potential therapeutic interventions. Our findings underscore the importance of considering K⁺ homeostasis in the development of targeted therapies for inflammatory conditions within the CNS.

potassium
homeostasis
inflammation
neurons
glia
neurodegeneration

Potassium ions (K⁺) are central to cell physiology, playing an important role in cell electrophysiology, especially in preserving resting membrane potential and in producing action potentials in the nervous system and heart ^[1]. K⁺ is actively transported into cells by sodium potassium adenosine triphosphatase (Na, K-ATPase; Na⁺ pump), which maintains intracellular K⁺ at least 30-fold greater than extracellular K⁺. Intracellular K⁺ concentration ([K⁺]i) is normally 150 mM, while the extracellular concentration can range from 3.5 to 5.0 mM depending on the physiological setting ^[2].

K⁺ is a key player in neuronal excitability and signalling, playing an essential role in various physiological processes within the central nervous system. However, emerging evidence suggests that disturbances in K⁺ homeostasis can have profound implications for inflammatory processes and contribute to the pathogenesis of neurological disorders characterised by chronic inflammation ^[3]^[4].

Inflammation within the brain is a complex cascade of immune responses involving distinct cellular and molecular entities ^[5]^[6]^[7]. Inflammation exists as a double-edged sword aiming to protect against injury and infection, however dysregulated or persistent inflammation can induce detrimental effects on neuronal function and contribute to the development and progression of neuroinflammatory disorders.

Studies have demonstrated the intricate interplay between K⁺ homeostasis and inflammation within the brain ^[8]^[9]^[10]. Disruptions in K⁺ dynamics, whether due to impaired ion channel function, altered transporter activity, or dysregulated extracellular K⁺ levels, have been implicated in triggering and perpetuating inflammatory processes. Conversely, inflammatory mediators released during inflammation can influence potassium ion channels and transporters, leading to imbalances in K⁺ homeostasis.

This article aims to explore the complex relationship between potassium ion homeostasis and inflammation in the brain. It seeks to highlight the compendium of molecular mechanisms proposed to underly the crosstalk between these two fundamental processes and shed light on their implications for inflammatory disorders. By elucidating the intricate regulatory cellular and molecular networks involved, it provides a comprehensive understanding of how disruptions in brain K⁺ homeostasis contribute to inflammation and strategies to modify this.

In conclusion, understanding the intricate interplay between potassium ion homeostasis and inflammation in the brain is pivotal for unravelling the underlying mechanisms of inflammatory disorders. This review aims to contribute to the growing body of knowledge surrounding the complex relationship between K⁺ dynamics and inflammatory signalling in the brain with the goal of identifying potential therapeutic strategies for modulating K⁺ homeostasis and ameliorating inflammatory cascades. To accomplish these objectives, this research paper will critically analyse and review the existing literature, incorporating data from in vitro and in vivo studies, animal models, and preclinical investigations. Shedding light on this intricate relationship could open new avenues for targeted interventions in the treatment of brain diseases, where inflammation is known to play a role.

This entry is adapted from the peer-reviewed paper 10.3390/encyclopedia4040110

References

Kettritz, R.; Loffing, J. Potassium homeostasis—Physiology and pharmacology in a clinical context. Pharmacol. Ther. 2023, 249, 108489.
Mcdonough, A.A.; Fenton, R.A. Potassium homeostasis: Sensors, mediators, and targets. Pflügers Arch.-Eur. J. Physiol. 2022, 474, 853–867.
Schmaul, S.; Hanuscheck, N.; Bittner, S. Astrocytic potassium and calcium channels as integrators of the inflammatory and ischemic CNS microenvironment. Biol. Chem. 2021, 402, 1519–1530.
Sahranavard, T.; Carbone, F.; Montecucco, F.; Xu, S.; Al-Rasadi, K.; Jamialahmadi, T.; Sahebkar, A. The role of potassium in atherosclerosis. Eur. J. Clin. Investig. 2021, 51, e13454.
Dantzer, R.; O’Connor, J.C.; Freund, G.G.; Johnson, R.W.; Kelley, K.W. From inflammation to sickness and depression: When the immune system subjugates the brain. Nat. Rev. Neurosci. 2008, 9, 46–56.
Galea, I. The blood–brain barrier in systemic infection and inflammation. Cell. Mol. Immunol. 2021, 18, 2489–2501.
Zhang, W.; Xiao, D.; Mao, Q.; Xia, H. Role of neuroinflammation in neurodegeneration development. Signal Transduct. Target. Ther. 2023, 8, 267.
Fujikawa, D.G.; Kim, J.S.; Daniels, A.H.; Alcaraz, A.F.; Sohn, T.B. In vivo elevation of extracellular potassium in the rat amygdala increases extracellular glutamate and aspartate and damages neurons. Neuroscience 1996, 74, 695–706.
Villa, C.; Suphesiz, H.; Combi, R.; Akyuz, E. Potassium channels in the neuronal homeostasis and neurodegenerative pathways underlying Alzheimer’s disease: An update. Mech. Ageing Dev. 2020, 185, 111197.
Ding, F.; Sun, Q.; Long, C.; Rasmussen, R.N.; Peng, S.; Xu, Q.; Kang, N.; Song, W.; Weikop, P.; Goldman, S.A.; et al. Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration. Brain 2024, 147, 1726–1739.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.