Potassium channels participate in many biological functions, from ion homeostasis to generation and modulation of the electrical membrane potential. They are involved in a large variety of diseases. ...In the human genome, 15 genes code for K+ channels with two pore domains (K2P). These channels form dimers of pore‐forming subunits that produce background conductances finely regulated by a range of natural and chemical effectors, including signalling lipids, temperature, pressure, pH, antidepressants and volatile anaesthetics. Since the cloning of TWIK1, the prototypical member of this family, a lot of work has been carried out on their structure and biology. These studies are still in progress, but data gathered so far show that K2P channels are central players in many processes, including ion homeostasis, hormone secretion, cell development and excitability. A growing number of studies underline their implication in physiopathological mechanisms, such as vascular and pulmonary hypertension, cardiac arrhythmias, nociception, neuroprotection and depression. This review gives a synthetic view of the most noticeable features of these channels.
Background or leak conductances are a major determinant of membrane resting potential and input resistance, two key components of neuronal excitability. The primary structure of the background K
+ ...channels has been elucidated. They form a family of channels that are molecularly and functionally divergent from the voltage-gated K
+ channels and inward rectifier K
+ channels. In the nervous system, the main representatives of this family are the TASK and TREK channels. They are relatively insensitive to the broad-spectrum K
+ channel blockers tetraethylammonium (TEA), 4-aminopyridine (4-AP), Cs
+, and Ba
2+. They display very little time- or voltage-dependence. Open at rest, they are involved in the maintenance of the resting membrane potential in somatic motoneurones, brainstem respiratory and chemoreceptor neurones , and cerebellar granule cells. TASK and TREK channels are also the targets of many physiological stimuli, including intracellular and extracellular pH and temperature variations, hypoxia, bioactive lipids, and neurotransmitter modulation. Integration of these different signals has major effects on neuronal excitability. Activation of some of these channels by volatile anaesthetics and by other neuroprotective agents, such as riluzole and unsaturated fatty acids, illustrates how the neuronal background K
+ conductances are attractive targets for the development of new drugs.
It is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant ...negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents. These findings identify TREK1 and TREK2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations.
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•TRESK, a K2P channel implicated in migraine, heteromerizes with TREK1 and TREK2•Migraine-associated TRESK-MT mutant induces formation of two proteins: MT1 and MT2•MT2 is produced by frameshift mutation-induced alternative translation initiation•MT2 inhibits TREK to increase neuronal excitability and induce a migraine phenotype
Royal et al. demonstrate that migraine-associated frameshift mutations of TRESK, a two-pore-domain K+ channel, lead to the production of a second protein fragment, which carries the pathophysiological function by inhibiting TREK1 and 2, due to a mechanism called frameshift mutation-induced alternative translation initiation (fsATI).
ABSTRACT
External acidity induces catecholamine secretion by inhibiting TASK1‐like channels in rat adrenal medullary (AM) cells. TASK channels can function as a heteromer or homomer in the TASK ...subfamily. In this study, we elucidate the molecular identity of TASK1‐like channels in mouse AM cells using gene knockout. Genetic deletion of TASK1, but not TASK3, abolished the depolarizing inward current and catecholamine secretion in response to acidity, whereas it did not affect the resting current level. Immunocytochemistry revealed that AM cells exhibited predominantly TASK1‐like and little TASK3‐like immunoreactivity. A proximity ligation assay showed that TASK1/3 heteromeric channels were not formed in AM cells or PC12 cells. However, the exogenous expression of p11 in PC12 cells resulted in the heteromeric formation of TASK isoforms, which were mainly located in the cytoplasm, and p11 was not expressed in rat adrenal medullae or PC12 cells. In AM cells, genetic deletion of TASK1 resulted in enhancement of the immunoreactivity of the TALK2 channel, but not TASK3. The results indicate that TASK1 homomeric channels function as acidity sensors in AM cells, and that function is facilitated by the lack of p11 expression.—Inoue, M., Matsuoka, H., Lesage, F., Harada, K. Lack of p11 expression facilitates acidity‐sensing function of TASK1 channels in mouse adrenal medullary cells. FASEB J. 33, 455–468 (2019). www.fasebj.org
Potassium channels form the largest family of ion channels with more than 80 members involved in cell excitability and signalling. Most of them exist as homomeric channels, whereas specific ...conditions are required to obtain heteromeric channels. It is well established that heteromerization of voltage‐gated and inward rectifier potassium channels affects their function, increasing the diversity of the native potassium currents. For potassium channels with two pore domains (K2P), homomerization has long been considered the rule, their polymodal regulation by a wide diversity of physical and chemical stimuli being responsible for the adaptation of the leak potassium currents to cellular needs. This view has recently evolved with the accumulation of evidence of heteromerization between different K2P subunits. Several functional intragroup and intergroup heteromers have recently been identified, which contribute to the functional heterogeneity of this family. K2P heteromerization is involved in the modulation of channel expression and trafficking, promoting functional and signalling diversity. As illustrated in the Figure, heteromerization of TREK1 and TRAAK provides the cell with more possibilities of regulation. It is becoming increasingly evident that K2P heteromers contribute to important physiological functions including neuronal and cardiac excitability. Since heteromerization also affects the pharmacology of K2P channels, this understanding helps to establish K2P heteromers as new therapeutic targets for physiopathological conditions.
figure legend TREK1 and TRAAK, two K2P channel subunits, assemble to form functional homodimers and heterodimers. Characterization of their regulations by protein kinase A and C, phospholipase D, intracellular and extracellular protons and chemical compounds such as ML67 and fluoxetine has shown that the TREK1/TRAAK heteromers have unique properties compared to TREK1 and TRAAK homomers.
Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial ...rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9
) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.
Highly selective for K
at neutral pH, the TWIK1 channel becomes permeable to Na
upon acidification. Using molecular dynamics simulations, we identify a network of residues involved in this unique ...property. Between the open and closed states previously observed by electron microscopy, molecular dynamics simulations show that the channel undergoes conformational changes between pH 7.5-6 involving residues His122, Glu235, Lys246 and Phe109. A complex network of interactions surrounding the selectivity filter at high pH transforms into a simple set of stronger interactions at low pH. In particular, His122 protonated by acidification moves away from Lys246 and engages in a salt bridge with Glu235. In addition, stacking interactions between Phe109 and His122, which stabilize the selectivity filter in its K
-selective state at high pH, disappear upon acidification. This leads to dissociation of the Phe109 aromatic side chain from this network, resulting in the Na
-permeable conformation of the channel.
Mutations that modulate the activity of ion channels are essential tools to understand the biophysical determinants that control their gating. Here, we reveal the conserved role played by a single ...amino acid position (TM2.6) located in the second transmembrane domain of two-pore domain potassium (K2P) channels. Mutations of TM2.6 to aspartate or asparagine increase channel activity for all vertebrate K2P channels. Using two-electrode voltage-clamp and single-channel recording techniques, we find that mutation of TM2.6 promotes channel gating via the selectivity filter gate and increases single channel open probability. Furthermore, channel gating can be progressively tuned by using different amino acid substitutions. Finally, we show that the role of TM2.6 was conserved during evolution by rationally designing gain-of-function mutations in four Caenorhabditis elegans K2P channels using CRISPR/Cas9 gene editing. This study thus describes a simple and powerful strategy to systematically manipulate the activity of an entire family of potassium channels.
The tandem of pore domain in a weak inwardly rectifying K⁺ channel (Twik)-related acid-arachidonic activated K⁺ channel (TRAAK) and Twik-related K⁺ channels (TREK) 1 and TREK2 are active as ...homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K2P) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs.
Two-pore domain background K(+) channels (K2p or KCNK) produce hyperpolarizing currents that control cell membrane polarity and neuronal excitability throughout the nervous system. The TREK2 channel ...as well as the related TREK1 and TRAAK channels are mechanical-, thermal- and lipid-gated channels that share many regulatory properties. TREK2 is one of the major background channels expressed in rodent nociceptive neurons of the dorsal root ganglia that innervate the skin and deep body tissues, but its role in somatosensory perception and nociception has remained poorly understood. We now report that TREK2 is a regulatory channel that controls the perception of non aversive warm, between 40°C and 46°C, and moderate ambient cool temperatures, between 20°C and 25°C, in mice. TREK2 controls the firing activity of peripheral sensory C-fibers in response to changes in temperature. The role of TREK2 in thermosensation is different from that of TREK1 and TRAAK channels; rather, TREK2, TREK1, and TRAAK channels appear to have complementary roles in thermosensation. TREK2 is also involved in mechanical pain perception and in osmotic pain after sensitization by prostaglandin E2. TREK2 is involved in the cold allodynia that characterizes the neuropathy commonly associated with treatments with the anticancer drug oxaliplatin. These results suggest that positive modulation of the TREK2 channel may have beneficial analgesic effects in these neuropathic conditions.
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