Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels

Abstract

: Two-pore domain potassium (K2P) channels are a diverse family of potassium channels. K2P channels generate background leak potassium currents to regulate cellular excitability and are thereby involved in a wide range of neurological disorders. K2P channels are modulated by a variety of physicochemical factors such as mechanical stretch, temperature, and pH. In the the peripheral nervous system (PNS), K2P channels are widely expressed in nociceptive neurons and play a critical roles in pain perception. In this review, we summarize the recent advances in the pharmacological properties of K2P channels, with a focus on the exogenous small-molecule activators targeting K2P channels. We emphasize the subtype-selectivity, cellular and in vivo pharmacological properties of all the reported small-molecule activators. The key underlying analgesic mechanisms mediated by K2P are also summarized based on the data in the literature from studies using small-molecule activators and genetic knock-out animals. We discuss advantages and limitations of the translational perspectives of K2P in pain medicine and provide outstanding questions for future studies in the end.

Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets

“…K 2P channels can be regulated by diverse chemical, physical, and metabolic factors, such as extra- or intra-cellular pH, temperature, mechanical stimuli, G proteins, and signaling lipids [ 8 ]. They play an important role in stabilizing resting membrane conductance and repolarizing the action potential of excitable cells [ 9 ].…”

Progress in Neuropharmacology of Anesthetics and Analgesics for the Improvement of Medical Treatment

“…Besides general anesthesia, this thematic issue also contains some novel perspectives in analgesic pharmacology, particularly based on new ion channels. In the review by Lu Huang et al [ 9 ], the authors fully discuss the advantages and limitations of the translational perspectives of K2P (Two-pore domain potassium) channels in pain medicine and provide outstanding questions for future studies in the end. Besides this article in this thematic issue, another review in the previous issue by Daniel Cook and Peter Goldstein [ 10 ] is also relevant, which summarizes some non-canonical molecular targets for novel analgesics, such as ryanodine receptors (RyRs) and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.…”