Gating the pore of potassium leak channels

A key feature of potassium channel function is the ability to switch between conducting and non-conducting states by undergoing conformational changes in response to cellular or extracellular signals. Such switching is facilitated by the mechanical coupling of gating domain movements to pore opening and closing. Two-pore domain potassium channels (K_2P) conduct leak or background potassium-selective currents that are mostly time- and voltage-independent. These channels play a significant role in setting the cell resting membrane potential and, therefore modulate cell responsiveness and excitability. Thus, K_2P channels are key players in numerous physiological processes and were recently shown to also be involved in human pathologies. It is well established that K_2P channel conductance, open probability and cell surface expression are significantly modulated by various physical and chemical stimuli. However, in understanding how such signals are translated into conformational changes that open or close the channels gate, there remain more open questions than answers. A growing line of evidence suggests that the outer pore area assumes a critical role in gating K_2P channels, in a manner reminiscent of C-type inactivation of voltage-gated potassium channels. In some K_2P channels, this gating mechanism is facilitated in response to external pH levels. Recently, it was suggested that K_2P channels also possess a lower activation gate that is positively coupled to the outer pore gate. The purpose of this review is to present an up-to-date summary of research describing the conformational changes and gating events that take place at the K_2P channel ion-conducting pathway during the channel regulation.     

Multiple modalities converge on a common gate to control K2P channel function

Members of the K_2P potassium channel family regulate neuronal excitability and are implicated in pain, anaesthetic responses, thermosensation, neuroprotection, and mood. Unlike other potassium channels, K_2Ps are gated by remarkably diverse stimuli that include chemical, thermal, and mechanical modalities. It has remained unclear whether the various gating inputs act through separate or common channel elements. Here, we show that protons, heat, and pressure affect activity of the prototypical, polymodal K_2P, K_2P2.1 (KCNK2/TREK‐1), at a common molecular gate that comprises elements of the pore‐forming segments and the N‐terminal end of the M4 transmembrane segment. We further demonstrate that the M4 gating element is conserved among K_2Ps and is employed regardless of whether the gating stimuli are inhibitory or activating. Our results define a unique gating mechanism shared by K_2P family members and suggest that their diverse sensory properties are achieved by coupling different molecular sensors to a conserved core gating apparatus.     

The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide and fatty acid metabolism

Work over the past three decades has greatly advanced our understanding of the regulation of K_ir K⁺ channels by polyanionic lipids of the phosphoinositide (e.g., PIP₂) and fatty acid metabolism (e.g., oleoyl-CoA). However, comparatively little is known regarding the regulation of the K_2P channel family by phosphoinositides and by long-chain fatty acid–CoA esters, such as oleoyl-CoA. We screened 12 mammalian K_2P channels and report effects of polyanionic lipids on all tested channels. We observed activation of members of the TREK, TALK, and THIK subfamilies, with the strongest activation by PIP₂ for TRAAK and the strongest activation by oleoyl-CoA for TALK-2. By contrast, we observed inhibition for members of the TASK and TRESK subfamilies. Our results reveal that TASK-2 channels have both activatory and inhibitory PIP₂ sites with different affinities. Finally, we provided evidence that PIP₂ inhibition of TASK-1 and TASK-3 channels is mediated by closure of the recently identified lower X-gate as critical mutations within the gate (i.e., L244A, R245A) prevent PIP₂-induced inhibition. Our findings establish that K⁺ channels of the K_2P family are highly sensitive to polyanionic lipids, extending our knowledge of the mechanisms of lipid regulation and implicating the metabolism of these lipids as possible effector pathways to regulate K_2P channel activity.     

Identification and functional characterization of zebrafish K2P10.1 (TREK2) two-pore-domain K+ channels

Two-pore-domain potassium (K_2P) channels mediate K⁺ background currents that stabilize the resting membrane potential and contribute to repolarization of action potentials in excitable cells. The functional significance of K_2P currents in cardiac electrophysiology remains poorly understood. Danio rerio (zebrafish) may be utilized to elucidate the role of cardiac K_2P channels in vivo. The aim of this work was to identify and functionally characterize a zebrafish otholog of the human K_2P10.1 channel. K_2P10.1 orthologs in the D. rerio genome were identified by database analysis, and the full zK_2P10.1 coding sequence was amplified from zebrafish cDNA. Human and zebrafish K_2P10.1 proteins share 61% identity. High degrees of conservation were observed in protein domains relevant for structural integrity and regulation. K_2P10.1 channels were heterologously expressed in Xenopus oocytes, and currents were recorded using two-electrode voltage clamp electrophysiology. Human and zebrafish channels mediated K⁺ selective background currents leading to membrane hyperpolarization. Arachidonic acid, an activator of hK_2P10.1, induced robust activation of zK_2P10.1. Activity of both channels was reduced by protein kinase C. Similar to its human counterpart, zK_2P10.1 was inhibited by the antiarrhythmic drug amiodarone. In summary, zebrafish harbor K_2P10.1 two-pore-domain K⁺ channels that exhibit structural and functional properties largely similar to human K_2P10.1. We conclude that the zebrafish represents a valid model to study K_2P10.1 function in vivo.     

Two-pore potassium channels in the cardiovascular system

Two-pore domain (K_2P) channels emerged about a decade ago and since then have been an expanding area of interest. This is because their biophysical and pharmacological properties make them good candidates to support background potassium currents and membrane potential in many cell types. There is clear evidence for TREK-1 and TASK-1 in the heart and these channels are likely to regulate cardiac action potential duration through their regulation by stretch, polyunsaturated fatty acids, pH, and neurotransmitters. TREK-1 may also have a critical role in mediating the vasodilator response of resistance arteries to polyunsaturated fatty acids, thus contributing to their protective effect on the cardiovascular system. TASK-1, on the other hand, is a strong candidate for a role in hypoxic vasoconstriction of pulmonary arteries. Many other members of the K_2P channel family have been identified in the cardiovascular system, although their functional roles are still to be demonstrated. This review provides an up to date summary of what is known about the involvement of members of the K_2P channel family in cells of the heart and arterial circulation. Our knowledge of their roles will improve with the rapidly increasing interest in them and as new selective pharmacological tools emerge. As their physiological roles emerge, the K_2P family of potassium channels may offer promising therapeutic solutions to target cardiovascular diseases. EBSA satellite meeting: ion channels, Leeds, July 2007.     

Acid sensitive background potassium channels K2P3.1 and K2P9.1 undergo rapid dynamin-dependent endocytosis

Acid-sensitive, two-pore domain potassium channels, K_2P3.1 and K_2P9.1, are implicated in cardiac and nervous tissue responses to hormones, neurotransmitters and drugs. K_2P3.1 and K_2P9.1 leak potassium from the cell at rest and directly impact membrane potential. Hence altering channel number on the cell surface drives changes in cellular electrical properties. The rate of K_2P3.1 and K_2P9.1 delivery to and recovery from the plasma membrane determines both channel number at the cell surface and potassium leak from cells. This study examines the endocytosis of K_2P3.1 and K_2P9.1. Plasma membrane biotinylation was used to follow the fate of internalized GFP-tagged rat K_2P3.1 and K_2P9.1 transiently expressed in HeLa cells. Confocal fluorescence images were analyzed using Imaris software, which revealed that both channels are endocytosed by a dynamin-dependent mechanism and over the course of 60 min, move progressively toward the nucleus. Endogenous endocytosis of human K_2P3.1 and K_2P9.1 was examined in the lung carcinoma cell line, A549. Endogenous channels are endocytosed over a similar time-scale to the channels expressed transiently in HeLa cells. These findings both validate the use of recombinant systems and identify an endogenous model system in which K_2P3.1 and K_2P9.1 trafficking can be further studied.     

N-Glycosylation-dependent Control of Functional Expression of Background Potassium Channels K2P3.1 and K2P9.1

Two-pore domain potassium (K_2P) channels play fundamental roles in cellular processes by enabling a constitutive leak of potassium from cells in which they are expressed, thus influencing cellular membrane potential and activity. Hence, regulation of these channels is of critical importance to cellular function. A key regulatory mechanism of K_2P channels is the control of their cell surface expression. Membrane protein delivery to and retrieval from the cell surface is controlled by their passage through the secretory and endocytic pathways, and post-translational modifications regulate their progression through these pathways. All but one of the K_2P channels possess consensus N-linked glycosylation sites, and here we demonstrate that the conserved putative N-glycosylation site in K_2P3.1 and K_2P9.1 is a glycan acceptor site. Patch clamp analysis revealed that disruption of channel glycosylation reduced K_2P3.1 current, and flow cytometry was instrumental in attributing this to a decreased number of channels on the cell surface. Similar findings were observed when cells were cultured in reduced glucose concentrations. Disruption of N-linked glycosylation has less of an effect on K_2P9.1, with a small reduction in number of channels on the surface observed, but no functional implications detected. Because nonglycosylated channels appear to pass through the secretory pathway in a manner comparable with glycosylated channels, the evidence presented here suggests that the decreased number of nonglycosylated K_2P3.1 channels on the cell surface may be due to their decreased stability.     

Kv12.1 channels are not sensitive to GqPCR-triggered activation of phospholipase Cβ

K_v12.1 K⁺ channels are expressed in several brain areas, but no physiological function could be attributed to these subunits so far. As genetically-modified animal models are not available, identification of native K_v12.1 currents must rely on characterization of distinct channel properties. Recently, it was shown in Xenopus laevis oocytes that K_v12.1 channels were modulated by membrane PI(4,5)P₂. However, it is not known whether these channels are also sensitive to physiologically-relevant PI(4,5)P₂ dynamics. We thus studied whether K_v12.1 channels were modulated by activation of phospholipase C β (PLCβ) and found that they were insensitive to receptor-triggered depletion of PI(4,5)P₂. Thus, K_v12.1 channels add to the growing list of K⁺ channels that are insensitive to PLCβ signaling, although modulated by PI(4,5)P₂ in Xenopus laevis oocytes.     

Novel Kv7.1-Phosphatidylinositol 4,5-Bisphosphate Interaction Sites Uncovered by Charge Neutralization Scanning

K_v7.1 to K_v7.5 α-subunits belong to the family of voltage-gated potassium channels (K_v). Assembled with the β-subunit KCNE1, K_v7.1 conducts the slowly activating potassium current I_Ks, which is one of the major currents underlying repolarization of the cardiac action potential. A known regulator of K_v7 channels is the lipid phosphatidylinositol 4,5-bisphosphate (PIP₂). PIP₂ increases the macroscopic current amplitude by stabilizing the open conformation of 7.1/KCNE1 channels. However, knowledge about the exact nature of the interaction is incomplete. The aim of this study was the identification of the amino acids responsible for the interaction between K_v7.1 and PIP₂. We generated 13 charge neutralizing point mutations at the intracellular membrane border and characterized them electrophysiologically in complex with KCNE1 under the influence of diC₈-PIP₂. Electrophysiological analysis of corresponding long QT syndrome mutants suggested impaired PIP₂ regulation as the cause for channel dysfunction. To clarify the underlying structural mechanism of PIP₂ binding, molecular dynamics simulations of K_v7.1/KCNE1 complexes containing two PIP₂ molecules in each subunit at specific sites were performed. Here, we identified a subset of nine residues participating in the interaction of PIP₂ and K_v7.1/KCNE1. These residues may form at least two binding pockets per subunit, leading to the stabilization of channel conformations upon PIP₂ binding.     

Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads

ATP-sensitive potassium (K_ATP) channels have the unique ability to adjust membrane excitability and functions in accordance with the metabolic status of the cell. Skeletal muscles are primary sites of activity-related energy consumption and have K_ATP channels expressed in very high density. Previously, we demonstrated that transgenic mice with skeletal muscle–specific disruption of K_ATP channel function consume more energy than wild-type littermates. However, how K_ATP channel activation modulates skeletal muscle resting and action potentials under physiological conditions, particularly low-intensity workloads, and how this can be translated to muscle energy expenditure are yet to be determined. Here, we developed a technique that allows evaluation of skeletal muscle excitability in situ, with minimal disruption of the physiological environment. Isometric twitching of the tibialis anterior muscle at 1 Hz was used as a model of low-intensity physical activity in mice with normal and genetically disrupted K_ATP channel function. This workload was sufficient to induce K_ATP channel opening, resulting in membrane hyperpolarization as well as reduction in action potential overshoot and duration. Loss of K_ATP channel function resulted in increased calcium release and aggravated activity-induced heat production. Thus, this study identifies low-intensity workload as a trigger for opening skeletal muscle K_ATP channels and establishes that this coupling is important for regulation of myocyte function and thermogenesis. These mechanisms may provide a foundation for novel strategies to combat metabolic derangements when energy conservation or dissipation is required.     

Effects of mono- and multi-valent cations on the inward-rectifying potassium channel in isolated protoplasts from maize roots

Transport properties mediated by ionic channels were studied by the patch-clamp technique in protoplasts from cortical parenchyma cells of maize roots (CPMR). While outward currents could be seen only occasionally, macroscopic voltage- and time-dependent potassium-selective inward currents (I_K+in) were frequently observed in the whole-cell configuration. These currents increased continuously as a function of K⁺ concentration (in the range 3 – 200 mm) and the slow-saturating macroscopic chord-conductance was fitted by a Michaelis-Menten function with K_m = 195 ± 39 mm. Other ions, like sodium and lithium, did not permeate at all through the maize root inward-channel, or like ammonium (P_NH4+/ P_K+ = 0.16 0.25) and rubidium (P_Rb+/P_K+≈ 0.10) displayed a very low permeability ratio. Up to 5 mm Rb⁺ did not induce any inhibition of the K⁺ inward current, whereas submillimolar concentrations of Cs⁺ were sufficient to block, in a voltage-dependent manner, the inward currents. A decrease of the external potassium concentration favoured Cs⁺ inhibition (K_m = 89 ± 6 μm and 26 ± 2 μm in 200 and 100 mm KCl, respectively). The potassium inward-currents were reversibly and consistently inhibited by submillimolar external concentrations of the metal ions Ni²⁺, Zn²⁺ and Co²⁺, while 1 mm La³⁺ only slightly decreased (≈10%) both the single channel conductance (9.2 ± 1.2 pS in 100 mm potassium) and the macroscopic current. In contrast to the case with Cs⁺, inhibition induced by other metal ions did not show any voltage dependence. These results suggest that, as with animal potassium channels, the inward channel of maize-root cortical cells has a narrow pore of permeation and metal ions decrease the K⁺ current, possibly by acting on binding sites located outside the pore. Received: 21 February 1997 / Accepted: 27 May 1997     

Molecular mechanism for depolarization-induced modulation of Kv channel closure

Voltage-dependent potassium (Kv) channels provide the repolarizing power that shapes the action potential duration and helps control the firing frequency of neurons. The K⁺ permeation through the channel pore is controlled by an intracellularly located bundle-crossing (BC) gate that communicates with the voltage-sensing domains (VSDs). During prolonged membrane depolarizations, most Kv channels display C-type inactivation that halts K⁺ conduction through constriction of the K⁺ selectivity filter. Besides triggering C-type inactivation, we show that in Shaker and Kv1.2 channels (expressed in Xenopus laevis oocytes), prolonged membrane depolarizations also slow down the kinetics of VSD deactivation and BC gate closure during the subsequent membrane repolarization. Measurements of deactivating gating currents (reporting VSD movement) and ionic currents (BC gate status) showed that the kinetics of both slowed down in two distinct phases with increasing duration of the depolarizing prepulse. The biphasic slowing in VSD deactivation and BC gate closure was strongly correlated in time and magnitude. Simultaneous recordings of ionic currents and fluorescence from a probe tracking VSD movement in Shaker directly demonstrated that both processes were synchronized. Whereas the first slowing originates from a stabilization imposed by BC gate opening, the subsequent slowing reflects the rearrangement of the VSD toward its relaxed state (relaxation). The VSD relaxation was observed in the Ciona intestinalis voltage-sensitive phosphatase and in its isolated VSD. Collectively, our results show that the VSD relaxation is not kinetically related to C-type inactivation and is an intrinsic property of the VSD. We propose VSD relaxation as a general mechanism for depolarization-induced slowing of BC gate closure that may enable Kv1.2 channels to modulate the firing frequency of neurons based on the depolarization history.     

Phosphate position is key in mediating transmembrane ion channel TMEM16A–phosphatidylinositol 4,5-bisphosphate interaction

TransMEMbrane 16A (TMEM16A) is a Ca²⁺-activated Cl⁻ channel that plays critical roles in regulating diverse physiologic processes, including vascular tone, sensory signal transduction, and mucosal secretion. In addition to Ca²⁺, TMEM16A activation requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂). However, the structural determinants mediating this interaction are not clear. Here, we interrogated the parts of the PI(4,5)P₂ head group that mediate its interaction with TMEM16A by using patch- and two-electrode voltage-clamp recordings on oocytes from the African clawed frog Xenopus laevis, which endogenously express TMEM16A channels. During continuous application of Ca²⁺ to excised inside–out patches, we found that TMEM16A-conducted currents decayed shortly after patch excision. Following this rundown, we show that the application of a synthetic PI(4,5)P₂ analog produced current recovery. Furthermore, inducible dephosphorylation of PI(4,5)P₂ reduces TMEM16A-conducted currents. Application of PIP₂ analogs with different phosphate orientations yielded distinct amounts of current recovery, and only lipids that include a phosphate at the 4′ position effectively recovered TMEM16A currents. Taken together, these findings improve our understanding of how PI(4,5)P₂ binds to and potentiates TMEM16A channels.     

Identification of endocrine cells of the stomach that express acid-sensitive background potassium (K<Subscript>2P</Subscript>9.1/TASK3) channels

The family of two-pore domain potassium (K_2P) channels is important in setting and controlling the background potassium current of excitable cells. This study examines the localisation of the acid-sensitive channel, K_2P9.1 (TASK3), in cells of the gastric mucosa. We observed K_2P9.1 immunoreactivity in endocrine cells of the mucosal glands of the guinea-pig, rat and mouse but the channels were not detected in parietal, chief, or mucous cells. K_2P9.1 channel immunoreactivity was consistently co-localised with histidine decarboxylase immunopositive enterochromaffin-like (ECL) cells, and with the majority of ghrelin immunoreactive X/A cells. Localisation in somatostatin immunoreactive D cells was rare in the guinea-pig, and did not occur in the stomach of rat, but, in the mouse, K_2P9.1 channels were observed in the majority of somatostatin-immunoreactive D cells. Conversely, sections taken from the guinea-pig and mouse stomachs, but not rat stomach, revealed K_2P9.1 in gastrin-containing G cells. These results demonstrate the presence of K_2P9.1 channels in the entero-endocrine ECL, G and D cell populations of the stomach that regulate acid secretion through the release of histamine, gastrin and somatostatin. K_2P9.1 channels were located in the ghrelin X/A cells that regulate food intake.     

Identification of two-pore domain potassium channels as potent modulators of osmotic volume regulation in human T lymphocytes

Many functions of T lymphocytes are closely related to cell volume homeostasis and regulation, which utilize a complex network of membrane channels for anions and cations. Among the various potassium channels, the voltage-gated K_V1.3 is well known to contribute greatly to the osmoregulation and particularly to the potassium release during the regulatory volume decrease (RVD) of T cells faced with hypotonic environment. Here we address a putative role of the newly identified two-pore domain (K_2P) channels in the RVD of human CD4⁺ T lymphocytes, using a series of potent well known channel blockers. In the present study, the pharmacological profiles of RVD inhibition revealed K_2P5.1 and K_2P18.1 as the most important K_2P channels involved in the RVD of both naïve and stimulated T cells. The impact of chemical inhibition of K_2P5.1 and K_2P18.1 on the RVD was comparable to that of K_V1.3. K_2P9.1 also notably contributed to the RVD of T cells but the extent of this contribution and its dependence on the activation status could not be unambiguously resolved. In summary, our data provide first evidence that the RVD-related potassium efflux from human T lymphocytes relies on K_2P channels.     

A structural model for K2P potassium channels based on 23 pairs of interacting sites and continuum electrostatics

K_2PØ, the two-pore domain potassium background channel that determines cardiac rhythm in Drosophila melanogaster, and its homologues that establish excitable membrane activity in mammals are of unknown structure. K_2P subunits have two pore domains flanked by transmembrane (TM) spans: TM1-P1-TM2-TM3-P2-TM4. To establish spatial relationships in K_2PØ, we identified pairs of sites that display electrostatic compensation. Channels silenced by the addition of a charge in pore loop 1 (P1) or P2 were restored to function by countercharges at specific second sites. A three-dimensional homology model was determined using the crystal structure of K_V1.2, effects of K_2PØ mutations to establish alignment, and compensatory charge–charge pairs. The model was refined and validated by continuum electrostatic free energy calculations and covalent linkage of introduced cysteines. K_2P channels use two subunits arranged so that the P1 and P2 loops contribute to one pore, identical P loops face each other diagonally across the pore, and the channel complex has bilateral symmetry with a fourfold symmetric selectivity filter.     

The Influence of Cold Temperature on Cellular Excitability of Hippocampal Networks

The hippocampus plays an important role in short term memory, learning and spatial navigation. A characteristic feature of the hippocampal region is its expression of different electrical population rhythms and activities during different brain states. Physiological fluctuations in brain temperature affect the activity patterns in hippocampus, but the underlying cellular mechanisms are poorly understood. In this work, we investigated the thermal modulation of hippocampal activity at the cellular network level. Primary cell cultures of mouse E17 hippocampus displayed robust network activation upon light cooling of the extracellular solution from baseline physiological temperatures. The activity generated was dependent on action potential firing and excitatory glutamatergic synaptic transmission. Involvement of thermosensitive channels from the transient receptor potential (TRP) family in network activation by temperature changes was ruled out, whereas pharmacological and immunochemical experiments strongly pointed towards the involvement of temperature-sensitive two-pore-domain potassium channels (K_2P), TREK/TRAAK family. In hippocampal slices we could show an increase in evoked and spontaneous synaptic activity produced by mild cooling in the physiological range that was prevented by chloroform, a K_2P channel opener. We propose that cold-induced closure of background TREK/TRAAK family channels increases the excitability of some hippocampal neurons, acting as a temperature-sensitive gate of network activation. Our findings in the hippocampus open the possibility that small temperature variations in the brain in vivo, associated with metabolism or blood flow oscillations, act as a switch mechanism of neuronal activity and determination of firing patterns through regulation of thermosensitive background potassium channel activity.     

Molecular Biology of Background K Channels: Insights from K2P Knockout Mice

K_2P channels are a family of cellular proteins that are essential for electrical signaling throughout the body. There are six K_2P channel subfamilies, consisting of 15 distinct mammalian genes. K_2P channels display a remarkable range of regulation by cellular, physical and pharmacologic agents, including protein kinases, intracellular Ca²⁺, changes in internal and external pH, anesthetic agents, heat, stretch and membrane deformers. The molecular and cellular mechanisms underlying this regulation are complex and cooperate at many different levels. Recent research has provided strong evidence that the spatiotemporal-specific expression of K_2P channels are determinants of physiologic selectivity and specificity. In recent years, knockout mice have been generated with inactivated K_2P channel genes. These animals shed new light on the contribution of K_2P channels to normal and abnormal physiology. In this review, we summarize the published data on these mice to broaden the understanding of the role of K_2P channel activity.     

Altered Expression of Two-Pore Domain Potassium (K2P) Channels in Cancer

Potassium channels have become a focus in cancer biology as they play roles in cell behaviours associated with cancer progression, including proliferation, migration and apoptosis. Two-pore domain (K_2P) potassium channels are background channels which enable the leak of potassium ions from cells. As these channels are open at rest they have a profound effect on cellular membrane potential and subsequently the electrical activity and behaviour of cells in which they are expressed. The K_2P family of channels has 15 mammalian members and already 4 members of this family (K_2P2.1, K_2P3.1, K_2P9.1, K_2P5.1) have been implicated in cancer. Here we examine the expression of all 15 members of the K_2P family of channels in a range of cancer types. This was achieved using the online cancer microarray database, Oncomine (www.oncomine.org). Each gene was examined across 20 cancer types, comparing mRNA expression in cancer to normal tissue. This analysis revealed all but 3 K_2P family members (K_2P4.1, K_2P16.1, K_2P18.1) show altered expression in cancer. Overexpression of K_2P channels was observed in a range of cancers including breast, leukaemia and lung while more cancers (brain, colorectal, gastrointestinal, kidney, lung, melanoma, oesophageal) showed underexpression of one or more channels. K_2P1.1, K_2P3.1, K_2P12.1, were overexpressed in a range of cancers. While K_2P1.1, K_2P3.1, K_2P5.1, K_2P6.1, K_2P7.1 and K_2P10.1 showed significant underexpression across the cancer types examined. This analysis supports the view that specific K_2P channels may play a role in cancer biology. Their altered expression together with their ability to impact the function of other ion channels and their sensitivity to environmental stimuli (pO2, pH, glucose, stretch) makes understanding the role these channels play in cancer of key importance.