Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Group I metabotropic glutamate receptors (mGluRs) are implicated in diverse processes such as learning, memory, epilepsy, pain and neuronal death. By inhibiting background K(+) channels, group I mGluRs mediate slow and long-lasting excitation. The main neuronal representatives of this K(+) channel family (K(2P) or KCNK) are TASK and TREK. Here, we show that in cerebellar granule cells and in heterologous expression systems, activation of group I mGluRs inhibits TASK and TREK channels. D-myo-inositol-1,4,5-triphosphate and phosphatidyl-4,5-inositol-biphosphate depletion are involved in TASK channel inhibition, whereas diacylglycerols and phosphatidic acids directly inhibit TREK channels. Mechanisms described here with group I mGluRs will also probably stand for many other receptors of hormones and neurotransmitters.
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PMID:Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. 1453 13

The TREK-1 channel is a temperature-sensitive, osmosensitive and mechano-gated K+ channel with a regulation by Gs and Gq coupled receptors. This paper demonstrates that TREK-1 qualifies as one of the molecular sensors involved in pain perception. TREK-1 is highly expressed in small sensory neurons, is present in both peptidergic and nonpeptidergic neurons and is extensively colocalized with TRPV1, the capsaicin-activated nonselective ion channel. Mice with a disrupted TREK-1 gene are more sensitive to painful heat sensations near the threshold between anoxious warmth and painful heat. This phenotype is associated with the primary sensory neuron, as polymodal C-fibers were found to be more sensitive to heat in single fiber experiments. Knockout animals are more sensitive to low threshold mechanical stimuli and display an increased thermal and mechanical hyperalgesia in conditions of inflammation. They display a largely decreased pain response induced by osmotic changes particularly in prostaglandin E2-sensitized animals. TREK-1 appears as an important ion channel for polymodal pain perception and as an attractive target for the development of new analgesics.
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PMID:TREK-1, a K+ channel involved in polymodal pain perception. 1667 54

TREK channels are unique among two-pore-domain K(+) channels. They are activated by polyunsaturated fatty acids (PUFAs) including arachidonic acid (AA), phospholipids, mechanical stretch and intracellular acidification. They are inhibited by neurotransmitters and hormones. TREK-1 knockout mice have impaired PUFA-mediated neuroprotection to ischemia, reduced sensitivity to volatile anesthetics and altered perception of pain. Here, we show that the A-kinase-anchoring protein AKAP150 is a constituent of native TREK-1 channels. Its binding to a key regulatory domain of TREK-1 transforms low-activity outwardly rectifying currents into robust leak conductances insensitive to AA, stretch and acidification. Inhibition of the TREK-1/AKAP150 complex by Gs-coupled receptors such as serotonin 5HT4sR and noradrenaline beta2AR is as extensive as for TREK-1 alone, but is faster. Inhibition of TREK-1/AKAP150 by Gq-coupled receptors such as serotonin 5HT2bR and glutamate mGluR5 is much reduced when compared to TREK-1 alone. The association of AKAP150 with TREK channels integrates them into a postsynaptic scaffold where both G-protein-coupled membrane receptors (as demonstrated here for beta2AR) and TREK-1 dock simultaneously.
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PMID:AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels. 1711 Sep 24

TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family, share 65% amino acid sequence identity and some similar basic electrophysiological and pharmacological properties with TREK-1. It also has some specific regulatory pathway and tissue distribution contrasted with TREK-1 and TRAAK. TREK-2 distributes extensively in CNS and periphery tissue. It can be regulated by G-protein-coupled receptor (GPCR) and may involve in several of physiological and pathophysiological conditions. The long-chain unsaturated free fatty acids such as arachidonic acid (AA), PHi, pressure and temperature can increase the activity of TREK-2. The purpose of this review is to present the recent study and possible importance of TREK-2 in neuropathic pain, thereby emphasizing TREK-2 as one of the important mechanisms underlying. This information should be very useful and prospective for effective chronic pain therapy and future analgesic drug development. This review also further predicts the role of TREK-2 in brain ischemia, memory and other tissue. The specific location and function of TREK-2 in these tissues need further study.
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PMID:Recent advance and possible future in TREK-2: a two-pore potassium channel may involved in the process of NPP, brain ischemia and memory impairment. 1768 2

The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report that external acidification, within the physiological range, strongly inhibits the human K2P2.1 channel by inducing "C-type" closure. We have identified two histidine residues (i.e. His-87 and His-141), located in the first external loop of the channel, that govern the response of the channel to external pH. We demonstrate that these residues are within physical proximity to glutamate 84, homologous to Shaker Glu-418, KcsA Glu-51, and KCNK0 Glu-28 residues, all previously argued to stabilize the outer pore gate in the open conformation by forming hydrogen bonds with pore-adjacent residues. We thus propose a novel mechanism for pH sensing in which protonation of His-141 and His-87 generates a local positive charge that serves to draw Glu-84 away from its natural interactions, facilitating the collapse of the selectivity filter region. In accordance with this proposed mechanism, low pH modified K2P2.1 selectivity toward potassium. Moreover, the proton-mediated effect was inhibited by external potassium ions and was enhanced by a mutation (S164Y) known to accelerate C-type gating. Furthermore, proton-induced current inhibition was more pronounced at negative potentials. Thus, voltage-dependent C-type gating acceleration by protons represents a novel mechanism for K2P2.1 outward rectification.
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PMID:A novel mechanism for human K2P2.1 channel gating. Facilitation of C-type gating by protonation of extracellular histidine residues. 1847 99

Twik-related K+ (TREK) channels produce background currents that regulate cell excitability. In vivo, TREK-1 is involved in neuronal processes including neuroprotection against ischemia, general anesthesia, pain perception, and mood. Recently, we demonstrated that A-kinase anchoring protein AKAP150 binds to a major regulatory domain of TREK-1, promoting drastic changes in channel regulation by polyunsaturated fatty acids, pH, and stretch, and by G-protein-coupled receptors to neurotransmitters and hormones. Here, we show that the microtubule-associated protein Mtap2 is another constituent of native TREK channels in the brain. Mtap2 binding to TREK-1 and TREK-2 does not affect directly channel properties but enhances channel surface expression and current density. This effect relies on Mtap2 binding to microtubules. Mtap2 and AKAP150 interacting sites in TREK-1 are distinct and both proteins can dock simultaneously. Their effects on TREK-1 surface expression and activation are cumulative. In neurons, the three proteins are simultaneously detected in postsynaptic dense bodies. AKAP150 and Mtap2 put TREK channels at the center of a complex protein network that finely tunes channel trafficking, addressing, and regulation.
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PMID:Mtap2 is a constituent of the protein network that regulates twik-related K+ channel expression and trafficking. 1871 13

A distinct gene family of widely distributed and well-modulated two-pore-domain background potassium (K(2P)) channels establish resting membrane potential and cell excitability. By using new mouse models in which K(2P)-channel genes are deleted, the contributions of these channels to important physiological functions are now being revealed. Here, we highlight results of recent studies using mice deleted for K(2P)-channel subunits that uncover physiological functions of these channels, mostly those of the TASK and TREK subgroup. Consistent with activation of these K(2P) channels by volatile anesthetics, TASK-1, TASK-3 and TREK-1 contribute to anesthetic-induced hypnosis and immobilization. The acid-sensitive TASK channels are not required for brainstem control of breathing by CO(2) or pH, despite widespread expression in respiratory-related neurons. TASK channels are necessary, however, for homeostatic regulation of adrenal aldosterone secretion. The heat-, stretch- and lipid-activated TREK-1 channels contribute to temperature and mechanical pain sensation, neuroprotection by polyunsaturated fatty acids and, unexpectedly, mood regulation. The alkaline-activated TASK-2 channel is necessary for HCO(3)(-) reabsorption and osmotic volume regulation in kidney proximal tubule cells. Development of compounds that selectively modulate K(2P) channels is crucial for verifying these results and assessing the efficacy of therapies targeting these interesting channels.
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PMID:Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. 1882 65

TREK potassium channels belong to a family of channel subunits with two-pore domains (K(2P)). TREK1 knockout mice display impaired polyunsaturated fatty acid-mediated protection against brain ischemia, reduced sensitivity to volatile anesthetics, resistance to depression and altered perception of pain. Recently, we isolated native TREK1 channels from mouse brain and identified their specific components by mass spectrometry. Among the identified partners, the A-Kinase Anchoring Protein AKAP150 binds to a regulatory domain of TREK1 and acts as a molecular switch. It transforms low activity, outwardly rectifying TREK1 currents into robust leak conductances resistant to stimulation by arachidonic acid, membrane stretch and acidification. Inhibition of the TREK1/AKAP150 channel by Gs-coupled receptors is as extensive as for TREK1 alone (but faster) whereas inhibition of TREK1/AKAP150 by Gq-coupled receptors is reduced. Furthermore, the association of AKAP150 with TREK1 channels integrates them into postsynaptic scaffolds where G protein-coupled membrane receptors and channels dock simultaneously. This chapter describes the proteomic approach used to study the composition of native TREK1 channels and point out its advantages and limitations over more classical methods (two-hybrid screenings in the yeast and bacteria or GST-pull down).
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PMID:Protein complex analysis of native brain potassium channels by proteomics. 1899 88

Odontoblasts are organized as a single layer of specialized cells responsible for dentine formation and presumably for playing a role in tooth pain transmission. Each cell has an extension running into a dentinal tubule and bathing in the dentinal fluid. A dense network of sensory unmyelinated nerve fibers surrounds the cell bodies and processes. Thus, dentinal tubules subjected to external stimuli causing dentinal fluid movements and odontoblasts/nerve complex response may represent a unique mechano-sensory system giving to dentine-forming cells a pivotal role in signal transduction. Mediators of mechano-transduction identified in odontoblast include mechano-sensitive ion channels (high conductance calcium-activated potassium channel--K(Ca)--and a 2P domain potassium channel--TREK-1) and primary cilium. In many tissues, the latter is essential for microenvironment sensing but its role in the control of odontoblast behavior remains to be elucidated. Recent evidence for excitable properties and the concentration of key channels to the terminal web suggest that odontoblasts may operate as sensor cells.
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PMID:Odontoblast: a mechano-sensory cell. 1909 66

Pain is a physiological state promoting protective responses to harmful episodes. However, pain can become pathophysiological and become a chronic disruptive condition, damaging quality of life. The mammalian K(2P)2.1 (KCNK2, TREK-1) channel, expressed in sensory neurons of the dorsal root ganglia, was previously identified as a polymodal molecular sensor involved in pain perception. Here, we report that two pain-associated signals, external acidosis and lysophosphatidic acid (LPA), known to rise during injury, inflammation and cancer, profoundly down-modulate human K(2P)2.1 activity. The pH regulatory effect was mediated by activation of proton-sensitive G-protein coupled receptors and phospholipase C. Physiological concentrations of LPA overcame the effects of known K(2P)2.1 activators, such as arachidonic acid, lysophosphatidylcholine and temperature, by activating cell-surface receptors stimulating the G(q) pathway. Furthermore, we identified three K(2P)2.1 carboxy-terminal residues that mediate both pH and LPA regulatory effects. Our results highlight the important role of K(2P)2.1 channels as receptors for mediators known to cause nociception.
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PMID:Pain-associated signals, acidosis and lysophosphatidic acid, modulate the neuronal K(2P)2.1 channel. 1913 Aug 88


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