• Malaclemys terrapin centrata
• chromosome‐level genome assembly
• comparative genomics
• ion transport
• phylogeny
• salinity adaptation

• 32160135 National Natural Science Foundation of China Regional Fund Project
• 32322018 National Natural Science Foundation of China
• 32000383 National Natural Science Foundation of China
• 23GH02025 Fundamental Research Funds for the Central Universities
• G2022KY05105 Double First-Class Construction Special Fund
• 2023K-10 Foundation of Shaanxi Academy of Sciences

• Animals
• Humans
• Cold Temperature
• Thermosensing/physiology
• Ion Channels/metabolism
• Signal Transduction/physiology
• TRPM Cation Channels/metabolism
• Sensory Receptor Cells/physiology
• Sensory Receptor Cells/metabolism

• K01 NS124828 NINDS NIH HHS
• K01NS124828 NINDS NIH HHS

• potassium channels
• ion transport
• computational biophysics

• Potassium Channels, Tandem Pore Domain/metabolism
• Potassium Channels, Tandem Pore Domain/chemistry
• Potassium Channels, Tandem Pore Domain/genetics
• Molecular Dynamics Simulation
• Humans
• Phosphorylation
• Ion Channel Gating
• Protein Domains
• Cytosol/metabolism
• Animals
• HEK293 Cells
• Crystallography, X-Ray

• RU2518 Deutsche Forschungsgemeinschaft (German Research Foundation)
• EXC 2008/1-390540038 Deutsche Forschungsgemeinschaft (German Research Foundation)

• 5HT(1A) receptor
• Depression
• LTD
• Prelimbic cortex
• Synaptic plasticity
• TREK-1

• Rats
• Animals
• Neuronal Plasticity/physiology
• Cerebral Cortex
• Hippocampus/physiology
• Potassium Channels, Tandem Pore Domain/genetics
• Synaptic Transmission/physiology
• Prefrontal Cortex
• Antidepressive Agents/pharmacology
• Long-Term Synaptic Depression/physiology

• potassium channels
• cryoelectron microscopy
• ion transport

• Potassium Channels, Tandem Pore Domain/genetics
• Phospholipids
• Membrane Potentials
• Potassium/metabolism

• R35 GM137957 NIGMS NIH HHS
• R01 GM145918 NIGMS NIH HHS
• K08 GM132781 NIGMS NIH HHS
• S10 OD019994 NIH HHS
• R01 GM124451 NIGMS NIH HHS
• U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
• American Heart Association (American Heart Association, Inc.)

Two-pore domains potassium channel subunits, encoded by KCNK genes, play vital roles in breast cancer progression. However, the characteristics of most KCNK genes in breast cancer has yet to be clarified. In this study, we comprehensively analyzed the expression, alteration, prognosis, and biological functions of various KCNKs in breast cancer. The expression of KCNK1/4/6/9/10/13 were significantly upregulated, while KCNK2/3/5/7/17 were downregulated in breast cancer tissues compared to normal mammary tissues. Increased expression of KCNK1/3/4/9 was correlated with poor overall survival, while high expression of KCNK2/7/17 predicted better overall survival in breast cancer. Eight KCNK genes were altered in breast cancer patients with a genomic mutation rate ranged from 1.9% to 21%. KCNK1 and KCNK9 were the two most common mutations in breast cancer, occurred in 21% and 18% patients, respectively. Alteration of KCNK genes was associated with the worse clinical characteristics and higher TMB, MSI, and hypoxia score. Using machine learning method, a specific prognostic signature with seven KCNK genes was established, which manifested accuracy in predicting the prognosis of breast cancer in both training and validation cohorts. A nomogram with great predictive performance was afterwards constructed through incorporating KCNK-based risk score with clinical features. Furthermore, KCNKs were correlated with the activation of several tumor microenvironment cells, including T cells, mast cells, macrophages, and platelets. Presentation of antigen, stimulation of G protein signaling and toll-like receptor cascaded were regulated by KCNKs family. Taken together, KCNKs may regulate breast cancer progression via modulating immune response which can serve as ideal prognostic biomarkers for breast cancer patients. Our study provides novel insight for future studies evaluating their usefulness as therapeutic targets.

• National Natural Science Foundation of China

• Piezo
• mechanosensation
• mechanosensitive ion channels
• neural repair
• regeneration

In addition to the classical voltage-dependent behavior mediated by the voltage-sensing-domains (VSD) of ion channels, a growing number of voltage-dependent gating behaviors are being described in channels that lack canonical VSDs. A common thread in their mechanism of action is the contribution of the permeating ion to this voltage sensing process. The polymodal K2P K⁺ channel, TREK2 responds to membrane voltage through a gating process mediated by the interaction of K⁺ with its selectivity filter. Recently, we found that this action can be modulated by small molecule agonists (e.g. BL1249) which appear to have an electrostatic influence on K⁺ binding within the inner cavity and produce an increase in the single-channel conductance of TREK-2 channels. Here, we directly probed this K⁺-dependent gating process by recording both macroscopic and single-channel currents of TREK-2 in the presence of high concentrations of internal K⁺. Surprisingly we found TREK-2 is inhibited by high internal K⁺ concentrations and that this is mediated by the concomitant increase in ionic-strength. However, we were still able to determine that the increase in single channel conductance in the presence of BL1249 was blunted in high ionic-strength, whilst its activatory effect (on channel open probability) persisted. These effects are consistent with an electrostatic mechanism of action of negatively charged activators such as BL1249 on permeation, but also suggest that their influence on channel gating is complex.

• Anions
• Cell Membrane Permeability
• HEK293 Cells
• Humans
• Ion Channel Gating
• Osmolar Concentration
• Osmotic Pressure
• Potassium Channels, Tandem Pore Domain/metabolism
• Protein Conformation

• 109114/Z/15/Z Wellcome Trust
• BB/N009274/1 Biotechnology and Biological Sciences Research Council
• BB/S008608/1 Biotechnology and Biological Sciences Research Council
• wellcome trust
• biotechnology and biological sciences research council

• cellular neuroscience
• molecular neuroscience

• Alzheimer Disease
• Animals
• Cell Shape
• Collagen/metabolism
• Electrophysiology
• Extracellular Matrix Proteins/metabolism
• Female
• Glutamic Acid/metabolism
• Humans
• Lysine/analogs & derivatives
• Male
• Mice
• Neocortex/anatomy & histology
• Neocortex/cytology
• Neocortex/growth & development
• Neurons/classification
• Neurons/cytology
• Neurons/metabolism
• Patch-Clamp Techniques
• Transcriptome

• U01 MH114812 NIMH NIH HHS
• R01 NS120300 NINDS NIH HHS
• R01 EY023173 NEI NIH HHS
• P30 AG066509 NIA NIH HHS
• U01 MH105982 NIMH NIH HHS
• R01 MH116247 NIMH NIH HHS
• U19 MH114830 NIMH NIH HHS

• Calcium-activated
• Conductivity
• Gating
• Inwardly rectifying K
• Ion channel
• Potassium channel
• Selectivity
• Two-pore domain potassium
• Voltage-gated K

• Background current
• K2P channel
• KCNK
• TALK
• TASK
• THIK
• TRAAK
• TREK
• TRESK
• TWIK

• Humans
• Potassium Channels, Tandem Pore Domain/genetics

• R01 HL144615 NHLBI NIH HHS

• T32 GM008284 NIGMS NIH HHS
• R21 NS091941 NINDS NIH HHS
• R01 GM089740 NIGMS NIH HHS
• R21 GM100224 NIGMS NIH HHS
• R01 MH093603 NIMH NIH HHS
• R01 GM116961 NIGMS NIH HHS
• S10 OD021596 NIH HHS
• National Institute of Mental Health
• NIH Office of the Director
• National Institute of General Medical Sciences
• National Institute of Neurological Disorders and Stroke
• American Heart Association

Potassium K_2P (“leak”) channels conduct current across the entire physiological voltage range and carry leak or “background” currents that are, in part, time- and voltage-independent. The activity of K_2P channels affects numerous physiological processes, such as cardiac function, pain perception, depression, neuroprotection, and cancer development. We have recently established that, when expressed in Xenopus laevis oocytes, K_2P2.1 (TREK-1) channels are activated by several monoterpenes (MTs). Here, we show that, within a few minutes of exposure, other mechano-gated K_2P channels, K_2P4.1 (TRAAK) and K_2P10.1 (TREK-2), are opened by monoterpenes as well (up to an eightfold increase in current). Furthermor\e, carvacrol and cinnamaldehyde robustly enhance currents of the alkaline-sensitive K_2P5.1 (up to a 17-fold increase in current). Other members of the K_2P potassium channels, K_2P17.1, K_2P18.1, but not K_2P16.1, were also activated by various MTs. Conversely, the activity of members of the acid-sensitive (TASK) K_2P channels (K_2P3.1 and K_2P9.1) was rapidly decreased by monoterpenes. We found that MT selectively decreased the voltage-dependent portion of the current and that current inhibition was reduced with the elevation of external K⁺ concentration. These findings suggest that penetration of MTs into the outer leaflet of the membrane results in immediate changes at the selectivity filter of members of the TASK channel family. Thus, we suggest MTs as promising new tools for the study of K_2P channels’ activity in vitro as well as in vivo.

• K2P channel
• TALK
• TASK-1
• TRAAK
• TREK-1
• leak channels
• monoterpenes
• voltage-dependent current

• Carboxyl-terminal
• Carvacrol
• K(2P) channel
• KCNK2
• Monoterpenes
• PIP(2)
• Potassium leak channel
• TREK-1

• HCN channel
• TRP channel
• drug development
• pharmacology
• potassium channel
• sodium channel

• Animals
• Disease Susceptibility
• Drug Discovery
• Humans
• Ion Channel Gating
• Ion Channels/chemistry
• Ion Channels/genetics
• Ion Channels/metabolism
• Pain/drug therapy
• Pain/etiology
• Pain/metabolism

• Detrusor mechanosensitivity
• Micturition cycle
• TREK-1 channel
• Urinary bladder
• Voiding

The current knowledge of electrogenesis in mesenchymal stromal cells (MSCs) remains scarce. Earlier, we demonstrated that in MSCs from the human adipose tissue, transduction of certain agonists involved the phosphoinositide cascade. Its pivotal effector PLC generates DAG that can regulate ion channels directly or via its derivatives, including arachidonic acid (AA). Here we showed that AA strongly hyperpolarized MSCs by stimulating instantly activating, outwardly rectifying TEA-insensitive K⁺ channels. Among AA-regulated K⁺ channels, K2P channels from the TREK subfamily appeared to be an appropriate target. The expression of K2P channels in MSCs was verified by RT-PCR, which revealed TWIK-1, TREK-1, and TASK-5 transcripts. The TREK-1 inhibitor spadin antagonized the electrogenic action of AA, which was simulated by the channel activator BL 1249. This functional evidence suggested that TREK-1 channels mediated AA-dependent hyperpolarization of MSCs. Being mostly silent at rest, TREK-1 negligibly contributed to the “background” K⁺ current. The dramatic stimulation of TREK-1 channels by AA indicates their involvement in AA-dependent signaling in MSCs.

• TREK-1 channel
• arachidonic acid
• mesenchymal stromal cells
• patch clamp

Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Older invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive, but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.

PIEZO proteins form mechanosensitive ion channels. Here the authors present electrophysiological measurements that show that PIEZO channels are also modulated by voltage and can switch to a purely voltage gated mode, which is an evolutionary conserved property of this channel family.

• Anesthetic mechanisms
• HCN channel
• Heterologous expression
• K(2P) channel
• Patch clamp
• Two-electrode voltage clamp

TREK channels, which are gated open by a wide range of stimuli, exist in at least two conformations known as “up” and “down.” McClenaghan et al. show that the channel can be open in both of these conformations and that gating is primarily achieved by the channel’s selectivity filter.

The TREK subfamily of two-pore domain (K2P) K⁺ channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals.

• Adrenergic receptors
• Adrenergic signaling
• Patch-clamp
• TREK-2 channel current

• Cells, Cultured
• Electric Conductivity
• Fibroblasts/metabolism
• Humans
• Mastication/physiology
• Membrane Potentials/physiology
• Microscopy, Fluorescence
• Patch-Clamp Techniques
• Periodontal Ligament/cytology
• Periodontal Ligament/metabolism
• Potassium Channels, Tandem Pore Domain/biosynthesis
• Reverse Transcriptase Polymerase Chain Reaction
• Stress, Mechanical
• Up-Regulation

• Action Potentials/physiology
• Animals
• Cell Physiological Phenomena/physiology
• Humans
• Ion Channel Gating/physiology
• Neurons/metabolism
• Potassium/metabolism
• Potassium Channels, Tandem Pore Domain/chemistry
• Potassium Channels, Tandem Pore Domain/metabolism

• Escitalopram
• Poststroke depression
• TREK-1 (TWIK-related potassium channel, type 1)
• Therapeutic effects

• Cancer
• Metastasis
• Potassium channel
• Tumorigenesis

We tested the hypothesis that protein kinase A (PKA) inhibits K2P currents activated by protein kinase C (PKC) in freshly isolated aortic myocytes. PDBu, the PKC agonist, applied extracellularly, increased the amplitude of the K2P currents in the presence of the “cocktail” of K⁺ channel blockers. Gö 6976 significantly reduced the increase of the K2P currents by PDBu suggesting the involvement of either α or β isoenzymes of PKC. We found that forskolin, or membrane permeable cAMP, did not inhibit K2P currents activated by the PKC. However, when PKA agonists were added prior to PDBu, they produced a strong decrease in the K2P current amplitudes activated by PKC. Inhibition of PDBu-elicited K2P currents by cAMP agonists was not prevented by the treatment of vascular smooth muscle cells with PKA antagonists (H-89 and Rp-cAMPs). Zn²⁺ and Hg²⁺ inhibited K2P currents in one population of cells, produced biphasic responses in another population, and increased the amplitude of the PDBu-elicited K⁺ currents in a third population of myocytes, suggesting expression of several K2P channel types. We found that cAMP agonists inhibited biphasic responses and increase of amplitude of the PDBu-elicited K2P currents produced by Zn²⁺ and Hg². 6-Bnz-cAMp produced a significantly altered pH sensitivity of PDBu-elicited K2P-currents, suggesting the inhibition of alkaline-activated K2P-currents. These results indicate that 6-Bnz-cAMP and other cAMP analogs may inhibit K2P currents through a PKA-independent mechanism. cAMP analogs may interact with unidentified proteins involved in K2P channel regulation. This novel cellular mechanism could provide insights into the interplay between PKC and PKA pathways that regulate vascular tone.

• Animals
• Aorta/cytology
• Cell Separation
• Cyclic AMP/agonists
• Cyclic AMP/metabolism
• Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Hydrogen-Ion Concentration/drug effects
• Intracellular Space/drug effects
• Intracellular Space/metabolism
• Ion Channel Gating/drug effects
• Mercury/pharmacology
• Mice
• Mice, Inbred C57BL
• Muscle Cells/drug effects
• Muscle Cells/metabolism
• Muscle, Smooth, Vascular/cytology
• Phorbol 12,13-Dibutyrate/pharmacology
• Potassium Channel Blockers/pharmacology
• Potassium Channels/metabolism
• Protein Kinase C/metabolism
• Zinc/pharmacology

• SC2 HL107237 NHLBI NIH HHS
• HL107237 NHLBI NIH HHS

• TREK-1
• human
• pregnancy myometrium
• smooth muscle
• stretch-activated potassium channels
• uterus

• Adult
• Cell Line
• Female
• HEK293 Cells
• Humans
• Membrane Potentials/physiology
• Muscle Cells/metabolism
• Myocytes, Smooth Muscle/cytology
• Myocytes, Smooth Muscle/metabolism
• Myometrium/cytology
• Myometrium/metabolism
• Potassium/metabolism
• Potassium Channels/genetics
• Potassium Channels/metabolism
• Potassium Channels, Tandem Pore Domain/genetics
• Potassium Channels, Tandem Pore Domain/metabolism
• Pregnancy
• Tetraethylammonium/metabolism
• Up-Regulation
• Young Adult

• R01-HD-053028 NICHD NIH HHS

In whole cell patch clamp recordings, we found that normal human adrenal zona fasciculata (AZF) cells express voltage-gated, rapidly inactivating Ca²⁺ and K⁺ currents and a noninactivating, leak-type K⁺ current. Characterization of these currents with respect to voltage-dependent gating and kinetic properties, pharmacology, and modulation by the peptide hormones adrenocorticotropic hormone (ACTH) and AngII, in conjunction with Northern blot analysis, identified these channels as Ca_v3.2 (encoded by CACNA1H), Kv1.4 (KCNA4), and TREK-1 (KCNK2). In particular, the low voltage–activated, rapidly inactivating and slowly deactivating Ca²⁺ current (Ca_v3.2) was potently blocked by Ni²⁺ with an IC₅₀ of 3 µM. The voltage-gated, rapidly inactivating K⁺ current (Kv1.4) was robustly expressed in nearly every cell, with a current density of 95.0 ± 7.2 pA/pF (n = 64). The noninactivating, outwardly rectifying K⁺ current (TREK-1) grew to a stable maximum over a period of minutes when recording at a holding potential of −80 mV. This noninactivating K⁺ current was markedly activated by cinnamyl 1-3,4-dihydroxy-α-cyanocinnamate (CDC) and arachidonic acid (AA) and inhibited almost completely by forskolin, properties which are specific to TREK-1 among the K2P family of K⁺ channels. The activation of TREK-1 by AA and inhibition by forskolin were closely linked to membrane hyperpolarization and depolarization, respectively. ACTH and AngII selectively inhibited the noninactivating K⁺ current in human AZF cells at concentrations that stimulated cortisol secretion. Accordingly, mibefradil and CDC at concentrations that, respectively, blocked Ca_v3.2 and activated TREK-1, each inhibited both ACTH- and AngII-stimulated cortisol secretion. These results characterize the major Ca²⁺ and K⁺ channels expressed by normal human AZF cells and identify TREK-1 as the primary leak-type channel involved in establishing the membrane potential. These findings also suggest a model for cortisol secretion in human AZF cells wherein ACTH and AngII receptor activation is coupled to membrane depolarization and the activation of Ca_v3.2 channels through inhibition of hTREK-1.

A fundamental question in molecular neurobiology is how genes that determine basic neuronal properties shape the functional organization of brain circuits underlying complex learned behaviors. Given the growing availability of complete vertebrate genomes, comparative genomics represents a promising approach to address this question. Here we used genomics and molecular approaches to study how ion channel genes influence the properties of the brain circuitry that regulates birdsong, a learned vocal behavior with important similarities to human speech acquisition. We focused on potassium (K-)Channels, which are major determinants of neuronal cell excitability.

Starting with the human gene set of K-Channels, we used cross-species mRNA/protein alignments, and syntenic analysis to define the full complement of orthologs, paralogs, allelic variants, as well as novel loci not previously predicted in the genome of zebra finch (Taeniopygia guttata). We also compared protein coding domains in chicken and zebra finch orthologs to identify genes under positive selective pressure, and those that contained lineage-specific insertions/deletions in functional domains. Finally, we conducted comprehensive in situ hybridizations to determine the extent of brain expression, and identify K-Channel gene enrichments in nuclei of the avian song system.

We identified 107 K-Channel finch genes, including 6 novel genes common to non-mammalian vertebrate lineages. Twenty human genes are absent in songbirds, birds, or sauropsids, or unique to mammals, suggesting K-Channel properties may be lineage-specific. We also identified specific family members with insertions/deletions and/or high dN/dS ratios compared to chicken, a non-vocal learner. In situ hybridization revealed that while most K-Channel genes are broadly expressed in the brain, a subset is selectively expressed in song nuclei, representing molecular specializations of the vocal circuitry.

Together, these findings shed new light on genes that may regulate biophysical and excitable properties of the song circuitry, identify potential targets for the manipulation of the song system, and reveal genomic specializations that may relate to the emergence of vocal learning and associated brain areas in birds.

Two-pore domain K⁺ (K_2P) channels are thought to underlie background K⁺ conductance in many cell types. The Trek subfamily of K_2P channels consists of three members, Trek1/Kcnk2, Trek2/Kcnk10, and Traak/Kcnk4, all three of which are expressed in the rodent CNS. Constitutive ablation of the Trek1 gene in mice correlates with enhanced sensitivity to ischemia and epilepsy, decreased sensitivity to the effects of inhaled anesthetics, increased sensitivity to thermal and mechanical pain, and resistance to depression. While the distribution of Trek2 mRNA in the CNS is broad, little is known about the relevance of this Trek family member to neurobiology and behavior. Here, we probed the effect of constitutive Trek2 ablation, as well as the simultaneous constitutive ablation of all three Trek family genes, in paradigms that assess motor activity, coordination, anxiety-related behavior, learning and memory, and drug-induced reward-related behavior. No differences were observed between Trek2^−/− and Trek1/2/Traak^−/− mice in coordination or total distance traveled in an open-field. A gender-dependent impact of Trek ablation on open-field anxiety-related behavior was observed, as female but not male Trek2^−/− and Trek1/2/Traak^−/− mice spent more time in, and made a greater number of entries into, the center of the open-field than wild-type counterparts. Further evaluation of anxiety-related behavior in the elevated plus maze and light/dark box, however, did not reveal a significant influence of genotype on performance for either gender. Furthermore, Trek^−/− mice behaved normally in tests of learning and memory, including contextual fear conditioning and novel object recognition, and with respect to opioid-induced motor stimulation and conditioned place preference (CPP). Collectively, these data argue that despite their broad distribution in the CNS, Trek channels exert a minimal influence on a wide-range of behaviors.

• anxiety
• behavior
• knockout
• memory
• morphine
• potassium channel

Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties such as hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.

• General anesthesia
• Ion channels
• γ-amino-butyric acid type A receptors
• Hyperpolarization activated cyclic nucleotide
• Potassium channels
• Glutamatergic ion channels
• Sodium channels

The ability to sense mechanical, thermal, and chemical stimuli is critical to normal physiology and the perception of pain. Contact with noxious stimuli triggers a complex series of events that initiate innate protective mechanisms designed to minimize or avoid injury. Extreme temperatures, mechanical stress, and chemical irritants are detected by specific ion channels and receptors clustered on the terminals of nociceptive sensory nerve fibers and transduced into electrical information. Propagation of these signals, from distant sites in the body to the spinal cord and the higher processing centers of the brain, is also orchestrated by distinct groups of ion channels. Since their identification in 1995, evidence has emerged to support roles for K2P channels at each step along this pathway, as receptors for physiological and noxious stimuli, and as determinants of nociceptor excitability and conductivity. In addition, the many subtypes of K2P channels expressed in somatosensory neurons are also implicated in mediating the effects of volatile, general anesthetics on the central and peripheral nervous systems. Here, I offer a critical review of the existing data supporting these attributes of K2P channel function and discuss how diverse regulatory mechanisms that control the activity of K2P channels act to govern the operation of nociceptors.

• K1P18
• K2P1
• K2P10
• K2P2
• K2P3
• K2P4
• K2P9
• nociceptor