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TREK-1 K(+) channels in the cardiovascular system: their significance and potential as a therapeutic target
Lakshman Goonetilleke1, John Quayle
1School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
Insights
Potassium channels, particularly TREK-1, play a key role in cardiovascular health and disease. Modulating TREK-1 activity offers potential therapeutic strategies for cardiovascular conditions.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- Potassium (K+) channels are critical in cardiovascular disease, acting as both therapeutic targets and contributors to pathology.
- Voltage-dependent K+ (KV) channels are targeted by antiarrhythmic drugs, while K+ channel opening aids vasodilation and endothelial function.
Purpose of the Study:
- This review focuses on the two-pore domain K+ (K2P) channel, TREK-1, and its multifaceted roles in the cardiovascular system.
- To explore the regulation and physiological significance of TREK-1 in cardiovascular function and disease.
Main Methods:
- Review of existing literature on TREK-1 channel function, regulation, and its interaction with various physiological and pharmacological agents.
- Analysis of studies investigating TREK-1's role in vascular smooth muscle cells, endothelial function, and cardiac mechano-electrical coupling.
Main Results:
- TREK-1 activity is modulated by pH, stretch, polyunsaturated fatty acids (PUFAs), temperature, and signaling pathways.
- TREK-1 is activated by anesthetics and neuroprotectants, and inhibited by SSRIs and local anesthetics, suggesting a role in drug-induced cardiovascular effects.
- TREK-1 is implicated in cardiac mechano-electrical coupling and vascular responses to PUFAs, potentially explaining benefits of dietary fatty acids.
Conclusions:
- TREK-1 channels are significant regulators of cardiovascular function, influenced by diverse stimuli and drugs.
- Targeting TREK-1 with selective openers or inhibitors presents a promising avenue for novel cardiovascular disease interventions.
Abstract:
Potassium (K(+) ) channels are important in cardiovascular disease both as drug targets and as a cause of underlying pathology. Voltage-dependent K(+) (K(V) ) channels are inhibited by the class III antiarrhythmic agents. Certain vasodilators work by opening K(+) channels in vascular smooth muscle cells (VSMCs), and K(+) channel activation may also be a route to improving endothelial function. The two-pore domain K(+) (K(2P) ) channels form a group of 15 known channels with an expanding list of functions in the cardiovascular system. One of these K(2P) channels, TREK-1, is the focus of this review. TREK-1 channel activity is tightly regulated by intracellular and extracellular pH, membrane stretch, polyunsaturated fatty acids (PUFAs), temperature, and receptor-coupled second messenger systems. TREK-1 channels are also activated by volatile anesthetics and some neuroprotectant agents, and they are inhibited by selective serotonin reuptake inhibitors (SSRIs) as well as amide local anesthetics. Some of the clinical cardiovascular effects and side effects of these drugs may be through their actions on TREK-1 channels. It has recently been suggested that TREK-1 channels have a role in mechano-electrical coupling in the heart. They also seem important in the vascular responses to PUFAs, and this may underlie some of the beneficial cardiovascular effects of the essential dietary fatty acids. Development of selective TREK-1 openers and inhibitors may provide promising routes for intervention in cardiovascular diseases.
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