Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 61, 2021
Volume 61, Issue -, Pages 401-420Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-030920-111536
Keywords
K2P channel; inhalational anesthetic; negatively charged activators; cryptic binding site; TREK channels; TASK channels
Categories
Funding
- Biotechnology and Biological Sciences Research Council
- Royal Society
- LifeArc Centre for Therapeutics Discovery Award
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K2P channels play a crucial role in regulating cell activity and pharmacological modulation of these channels could be beneficial for various conditions. Recent studies on K2P channel structures and small-molecule compounds provide insights for the development of selective activators and inhibitors targeting these channels.
Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.
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