contributed equally to this work Aplysia S-type K ⍣ channels of sensory neurons play a dominant role in presynaptic facilitation and behavioural sensitization. They are closed by serotonin via cAMP-dependent phosphorylation, whereas they are opened by arachidonic acid, volatile general anaesthetics and mechanical stimulation. We have identified a cloned mammalian two P domain K ⍣ channel sharing the properties of the S channel. In addition, the recombinant channel is opened by lipid bilayer amphipathic crenators, while it is closed by cup-formers. The cytoplasmic C-terminus contains a charged region critical for chemical and mechanical activation, as well as a phosphorylation site required for cAMP inhibition.

TASK is a new member of the recently recognized TWIK K+ channel family. This 395 amino acid polypeptide has four transmembrane segments and two P domains. In adult human, TASK transcripts are found in pancreas

TREK-1 is a two-pore-domain background potassium channel expressed throughout the central nervous system. It is opened by polyunsaturated fatty acids and lysophospholipids. It is inhibited by neurotransmitters that produce an increase in intracellular cAMP and by those that activate the Gq protein pathway. TREK-1 is also activated by volatile anesthetics and has been suggested to be an important target in the action of these drugs. Using mice with a disrupted TREK-1 gene, we now show that TREK-1 has an important role in neuroprotection against epilepsy and brain and spinal chord ischemia. Trek1−/− mice display an increased sensitivity to ischemia and epilepsy. Neuroprotection by polyunsaturated fatty acids, which is impressive in Trek1+/+ mice, disappears in Trek1−/− mice indicating a central role of TREK-1 in this process. Trek1−/− mice are also resistant to anesthesia by volatile anesthetics. TREK-1 emerges as a potential innovative target for developing new therapeutic agents for neurology and anesthesiology

Human TWIK‐1, which has been cloned recently, is a new structural type of weak inward rectifier K+ channel. Here we report the structural and functional properties of TREK‐1, a mammalian TWIK‐1‐related K+ channel. Despite a low amino acid identity between TWIK‐1 and TREK‐1 (approximately 28%), both channel proteins share the same overall structural arrangement consisting of two pore‐forming domains and four transmembrane segments (TMS). This structural similarity does not give rise to a functional analogy. K+ currents generated by TWIK‐1 are inwardly rectifying while K+ currents generated by TREK‐1 are outwardly rectifying. These channels have a conductance of 14 pS. TREK‐1 currents are insensitive to pharmacological agents that block TWIK‐1 activity such as quinine and quinidine. Extensive inhibitions of TREK‐1 activity are observed after activation of protein kinases A and C. TREK‐1 currents are sensitive to extracellular K+ and Na+. TREK‐1 mRNA is expressed in most tissues and is particularly abundant in the lung and in the brain. Its localization in this latter tissue has been studied by in situ hybridization. TREK‐1 expression is high in the olfactory bulb, hippocampus and cerebellum. These results provide the first evidence for the existence of a K+ channel family with four TMS and two pore domains in the nervous system of mammals. They also show that different members in this structural family can have totally different functional properties.

A new human weakly inward rectifying K+ channel, TWIK‐1, has been isolated. This channel is 336 amino acids long and has four transmembrane domains. Unlike other mammalian K+ channels, it contains two pore‐forming regions called P domains. Genes encoding structural homologues are present in the genome of Caenorhabditis elegans. TWIK‐1 currents expressed in Xenopus oocytes are time‐independent and present a nearly linear I‐V relationship that saturated for depolarizations positive to O mV in the presence of internal Mg2+. This inward rectification is abolished in the absence of internal Mg2+. TWIK‐1 has a unitary conductance of 34 pS and a kinetic behaviour that is dependent on the membrane potential. In the presence of internal Mg2+, the mean open times are 0.3 and 1.9 ms at −80 and +80 mV, respectively. The channel activity is up‐regulated by activation of protein kinase C and down‐regulated by internal acidification. Both types of regulation are indirect. TWIK‐1 channel activity is blocked by Ba2+(IC50=100 microM), quinine (IC50=50 microM) and quinidine (IC50=95 microM). This channel is of particular interest because its mRNA is widely distributed in human tissues, and is particularly abundant in brain and heart. TWIK‐1 channels are probably involved in the control of background K+ membrane conductances.

The TREK-1 channel is a temperature-sensitive, osmosensitive and mechano-gated K þ 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 E 2 -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.

We investigated the role of PDZ proteins (GRIP, ABP, and PICK1) interacting with the C-terminal GluR2 by infusing a ct-GluR2 peptide ("pep2-SVKI") into CA1 pyramidal neurons in hippocampal slices using whole-cell recordings. Pep2-SVKI, but not a control or PICK1 selective peptide, caused AMPAR-mediated EPSC amplitude to increase in approximately one-third of control neurons and in most neurons following the prior induction of LTD. Pep2-SVKI also blocked LTD; however, this occurred in all neurons. A PKC inhibitor prevented these effects of pep2-SVKI on synaptic transmission and LTD. We propose a model in which the maintenance of LTD involves the binding of AMPARs to PDZ proteins to prevent their reinsertion. We also present evidence that PKC regulates AMPAR reinsertion during dedepression.

A complementary DNA encoding a novel K ؉ channel, called TASK-2, was isolated from human kidney and its gene was mapped to chromosome 6p21. TASK-2 has a low sequence similarity to other two pore domain K ؉ channels, such as TWIK-1, TREK-1, TASK-1, and TRAAK (18 -22% of amino acid identity), but a similar topology consisting of four potential membrane-spanning domains. In transfected cells, TASK-2 produces noninactivating, outwardly rectifying K ؉ currents with activation potential thresholds that closely follow the K ؉ equilibrium potential. As for the related TASK-1 and TRAAK channels, the outward rectification is lost at high external K ؉ concentration. The conductance of TASK-2 was estimated to be 14.5 picosiemens in physiological conditions and 59.9 picosiemens in symmetrical conditions with 155 mM K ؉ . TASK-2 currents are blocked by quinine (IC 50 ‫؍‬ 22 M) and quinidine (65% of inhibition at 100 M) but not by the other classical K ؉ channel blockers tetraethylammonium, 4-aminopyridine, and Cs ؉ . They are only slightly sensitive to Ba 2؉ , with less than 17% of inhibition at 1 mM. As TASK-1, TASK-2 is highly sensitive to external pH in the physiological range. 10% of the maximum current was recorded at pH 6.5 and 90% at pH 8.8. Unlike all other cloned channels with two pore-forming domains, TASK-2 is essentially absent in the brain. In human and mouse, TASK-2 is mainly expressed in the kidney, where in situ hybridization shows that it is localized in cortical distal tubules and collecting ducts. This localization, as well as its functional properties, suggest that TASK-2 could play an important role in renal K ؉ transport.