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.

TREK-1 (KCNK2 or K(2P)2.1) is a mechanosensitive K(2P) channel that is opened by membrane stretch as well as cell swelling. Here, we demonstrate that membrane phospholipids, including PIP(2), control channel gating and transform TREK-1 into a leak K(+) conductance. A carboxy-terminal positively charged cluster is the phospholipid-sensing domain that interacts with the plasma membrane. This region also encompasses the proton sensor E306 that is required for activation of TREK-1 by cytosolic acidosis. Protonation of E306 drastically tightens channel-phospholipid interaction and leads to TREK-1 opening at atmospheric pressure. The TREK-1-phospholipid interaction is critical for channel mechano-, pH(i)- and voltage-dependent gating.

We describe here several novel properties of the human ␣ 1G subunit that forms T-type calcium channels. The partial intron/exon structure of the corresponding gene CACNA1G was defined and several ␣ 1G isoforms were identified, especially two isoforms that exhibit a distinct III-IV loop: ␣ 1G-a and ␣ 1G-b . Northern blot and dot blot analyses indicated that ␣ 1G mRNA is predominantly expressed in the brain, especially in thalamus, cerebellum, and substantia nigra. Additional experiments have also provided evidence that ␣ 1G mRNA is expressed at a higher level during fetal life in nonneuronal tissues (i.e. kidney, heart, and lung). Functional expression in HEK 293 cells of a full-length cDNA encoding the shortest ␣ 1G isoform identified to date, ␣ 1G-b , resulted in transient, low threshold activated Ca 2؉ currents with the expected permeability ratio (I Sr > I Ca > I Ba ) and channel conductance (ϳ7 pS). These properties, together with slowly deactivating tail currents, are typical of those of native T-type Ca 2؉ channels. This ␣ 1G -related current was inhibited by mibefradil (IC 50 ‫؍‬ 2 M) and weakly blocked by Ni 2؉ ions (IC 50 ‫؍‬ 148 M) and amiloride (IC 50 > 1 mM). We showed that steady state activation and inactivation properties of this current can generate a "window current" in the range of ؊65 to ؊55 mV. Using neuronal action potential waveforms, we show that ␣ 1G channels produce a massive and sustained Ca 2؉ influx due to their slow deactivation properties. These latter properties would account for the specificity of Ca 2؉ influx via T-type channels that occurs in the range of physiological resting membrane potentials, differing considerably from the behavior of other Ca 2؉ channels.

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.