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Force sensing is a fundamental ability that allows cells and organisms to interact with their physical environment. The eye is constantly subjected to mechanical forces such as blinking and eye movements. Furthermore, elevated intraocular pressure (IOP) can cause mechanical strain at the optic nerve head, resulting in retinal ganglion cell death (RGC) in glaucoma. How mechanical stimuli are sensed and affect cellular physiology in the eye is unclear. Recent studies have shown that mechanosensitive ion channels are expressed in many ocular tissues relevant to glaucoma and may influence IOP regulation and RGC survival. Furthermore, variants in mechanosensitive ion channel genes may be associated with risk for primary open angle glaucoma. These findings suggest that mechanosensitive channels may be important mechanosensors mediating cellular responses to pressure signals in the eye. In this review, we focus on mechanosensitive ion channels from three major channel families-PIEZO, two-pore potassium and transient receptor potential channels. We review the key properties of these channels, their effects on cell function and physiology, and discuss their possible roles in glaucoma pathophysiology.
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Glaucoma , Presión Intraocular , Canales Iónicos , Mecanotransducción Celular , Células Ganglionares de la Retina , Humanos , Canales Iónicos/fisiología , Presión Intraocular/fisiología , Mecanotransducción Celular/fisiología , Glaucoma/fisiopatología , Células Ganglionares de la Retina/fisiología , Canales de Potencial de Receptor Transitorio/fisiología , AnimalesRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer type. PDAC is characterized by fibrotic, hypoxic, and presumably acidic tumor microenvironment (TME). Acidic TME is an important player in tumor development, progression, aggressiveness, and chemoresistance. The dysregulation of ductal ion transporters/channels might contribute to extracellular pH (pHe) acidification and PDAC progression. Our aim was to test whether H+/K+-ATPases and pH-sensitive K+ channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pHe conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H+/K+-ATPase inhibitor, alkalinized pHe. Second, we used FluoVolt to monitor the membrane voltage (Vm) and showed that riluzole hyperpolarized Vm, most likely by opening of pH-sensitive K+ channels such as TREK-1. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pHe conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co-targeting H+/K+-ATPases and pH-sensitive K+ channels by re-purposing of pantoprazole and riluzole could provide novel acidosis-targeted therapies of PDAC.
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Modulation of two-pore domain potassium (K2P) channels has emerged as a novel field of therapeutic strategies as they may regulate immune cell activation and metabolism, inflammatory signals, or barrier integrity. One of these ion channels is the TWIK-related potassium channel 1 (TREK1). In the current study, we report the identification and validation of new TREK1 activators. Firstly, we used a modified potassium ion channel assay to perform high-throughput-screening of new TREK1 activators. Dose-response studies helped to identify compounds with a high separation between effectiveness and toxicity. Inside-out patch-clamp measurements of Xenopus laevis oocytes expressing TREK1 were used for further validation of these activators regarding specificity and activity. These approaches yielded three substances, E1, B3 and A2 that robustly activate TREK1. Functionally, we demonstrated that these compounds reduce levels of adhesion molecules on primary human brain and muscle endothelial cells without affecting cell viability. Finally, we studied compound A2 via voltage-clamp recordings as this activator displayed the strongest effect on adhesion molecules. Interestingly, A2 lacked TREK1 activation in the tested neuronal cell type. Taken together, this study provides data on novel TREK1 activators that might be employed to pharmacologically modulate TREK1 activity.
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Canales de Potasio de Dominio Poro en Tándem , Humanos , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Células Endoteliales/metabolismo , Enfermedades Neuroinflamatorias , Encéfalo/metabolismo , Moléculas de Adhesión Celular/metabolismoRESUMEN
Potassium channels are widely distributed integral proteins responsible for the effective and selective transport of K+ ions through the biological membranes. According to the existing structural and mechanistic differences, they are divided into several groups. All of them are considered important molecular drug targets due to their physiological roles, including the regulation of membrane potential or cell signaling. One of the recent trends in molecular pharmacology is the evaluation of the therapeutic potential of natural compounds and their derivatives, which can exhibit high specificity and effectiveness. Among the pharmaceuticals of plant origin, which are potassium channel modulators, flavonoids appear as a powerful group of biologically active substances. It is caused by their well-documented anti-oxidative, anti-inflammatory, anti-mutagenic, anti-carcinogenic, and antidiabetic effects on human health. Here, we focus on presenting the current state of knowledge about the possibilities of modulation of particular types of potassium channels by different flavonoids. Additionally, the biological meaning of the flavonoid-mediated changes in the activity of K+ channels will be outlined. Finally, novel promising directions for further research in this area will be proposed.
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Hipoglucemiantes , Canales de Potasio , Humanos , Canales de Potasio/fisiología , PotasioRESUMEN
Mechanisms of synergistic agonist stimulation and modulation of the electrochemical driving force for anion secretion are still not fully explored in human pancreatic duct epithelial cells. The first objective of this study was therefore to test whether combined agonist stimulation augments anion transport responses in the Capan-1 monolayer model of human pancreatic duct epithelium. The second objective was to test the influence of H+,K+-ATPase inhibition on anion transport in Capan-1 monolayers. The third objective was to analyze the expression and function of K+ channels in Capan-1, which could support anion secretion and cooperate with H+,K+-ATPases in pH and potassium homeostasis. The human pancreatic adenocarcinoma cell line Capan-1 was cultured conventionally or as polarized monolayers that were analyzed by Ussing chamber electrophysiological recordings. Single-cell intracellular calcium was assayed with Fura-2. mRNA isolated from Capan-1 was analyzed by use of the nCounter assay or RT-PCR. Protein expression was assessed by immunofluorescence and western blot analyses. Combined stimulation with different physiological agonists enhanced anion transport responses compared to single agonist stimulation. The responsiveness of Capan-1 cells to histamine was also revealed in these experiments. The H+,K+-ATPase inhibitor omeprazole reduced carbachol- and riluzole-induced anion transport responses. Transcript analyses revealed abundant TASK-2, TWIK-1, TWIK-2, TASK-5, KCa3.1, and KCNQ1 mRNA expression. KCNE1 mRNA and TREK-1, TREK-2, TASK-2, and KCNQ1 protein expression were also shown. This study shows that the Capan-1 model recapitulates key physiological aspects of a bicarbonate-secreting epithelium and constitutes a valuable model for functional studies on human pancreatic duct epithelium.
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Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Adenocarcinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Conductos Pancreáticos , Células Epiteliales/metabolismo , Bicarbonatos/metabolismo , ARN Mensajero/metabolismo , Adenosina Trifosfatasas/metabolismoRESUMEN
Bacterial septicemia is commonly induced by Gram-negative bacteria. The immune response is triggered in part by the secretion of bacterial endotoxin lipopolysaccharide (LPS). LPS induces the subsequent release of inflammatory cytokines which can result in pathological conditions. There is no known blocker to the receptors of LPS. The Drosophila larval muscle is an amendable model to rapidly screen various compounds that affect membrane potential and synaptic transmission such as LPS. LPS induces a rapid hyperpolarization in the body wall muscles and depolarization of motor neurons. These actions are blocked by the compound doxapram (10 mM), which is known to inhibit a subtype of the two-P-domain K+ channel (K2P channels). However, the K2P channel blocker PK-THPP had no effect on the Drosophila larval muscle at 1 and 10 mM. These channels are activated by chloroform, which also induces a rapid hyperpolarization of these muscles, but the channels are not blocked by doxapram. Likewise, chloroform does not block the depolarization induced by doxapram. LPS blocks the postsynaptic glutamate receptors on Drosophila muscle. Pre-exposure to doxapram reduces the LPS block of these ionotropic glutamate receptors. Given that the larval Drosophila body wall muscles are depolarized by doxapram and hyperpolarized by chloroform, they offer a model to begin pharmacological profiling of the K2P subtype channels with the potential of identifying blockers for the receptors to mitigate the actions of the Gram-negative endotoxin LPS.
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Doxapram , Lipopolisacáridos , Animales , Doxapram/farmacología , Lipopolisacáridos/farmacología , Cloroformo , Transmisión Sináptica , DrosophilaRESUMEN
The TWIK-related spinal cord K+ channel (TRESK) is part of the two-pore domain K+ channel family (K2P), which are also called leak potassium channels. As indicated by the channel family name, TRESK conducts K+ ions along the concentration gradient in a nearly voltage-independent manner leading to lowered membrane potentials. Although functional and pharmacological similarities exist, TRESK shows low sequence identity with other K2P channels. Moreover, the channel possesses several unique features such as its sensitivity to intracellular Ca2+ ions, that are not found in other K2P channels. High expression rates are found in immune-associated and neuronal cells, especially in sensory neurons of the dorsal root and trigeminal ganglia. As a consequence of the induced hyperpolarization, TRESK influences neuronal firing, the release of inflammatory mediators and the proliferation of distinct immune cells. Consequently, this channel might be a suitable target for pharmacological intervention in migraine, epilepsy, neuropathic pain or distinct immune diseases. In this review, we summarize the biochemical and biophysical properties of TRESK channels as well as their sensitivity to different known compounds. Furthermore, we give a structured overview about the physiological and pathophysiological impact of TRESK, that render the channel as an interesting target for specific drug development.
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Canales de Potasio de Dominio Poro en Tándem , Potenciales de la Membrana/fisiología , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Neuronas/metabolismo , Médula Espinal/metabolismoRESUMEN
Since its discovery in the mid-20th century, the Hodgkin-Huxley biophysical model of the squid giant axon's (SGA's) neurophysiology has traditionally served as the basis for the teaching of action potential (AP) dynamics in the physiology classroom. This model teaches that leak conductances set membrane resting potential; that fast, inactivating, voltage-gated sodium channels effect the SGA AP upstroke; and that delayed, rectifying, noninactivating voltage-gated potassium channels carry AP repolarization and the early part of the afterhyperpolarization (AHP). This model serves well to introduce students to the fundamental ideas of resting potential establishment and maintenance, as well as basic principles of AP generation and propagation. Furthermore, the Hodgkin-Huxley SGA model represents an excellent and accessible starting point for discussion of the concept of AP threshold and the role of passive electrical properties of the neuron. Additionally, the introduction of the Hodgkin-Huxley model of the SGA AP permits the integration of physiological principles, as instructors ask students to apply previously studied principles of transporter and channel biophysics to the essential physiological phenomenon of electrical signal conduction. However, both some early observations as well as more recent evidence strongly suggest that this seminal invertebrate model of AP dynamics does not appropriately capture the full story for mammalian axons. We review recent evidence that mammalian axonal nodes of Ranvier repolarize largely (though not exclusively) through the activity of leak potassium-ion (K+) conductances carried through two-pore domain (K2P) channels. We call for changes to physiology textbooks and curricula to highlight this remarkable difference in invertebrate and mammalian AP repolarization mechanisms.NEW & NOTEWORTHY Historically, physiology courses have typically taught that action potential repolarization occurs exclusively due to the activation of delayed-rectifier voltage-gated potassium channels. Here, we review and highlight recent evidence that leak potassium channels of the two-pore domain (K2P) class may largely serve this repolarization role at mammalian nodes of Ranvier. We call for the inclusion of these ideas in physiology curricula at all levels, from high school to graduate school.
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Canales de Potasio de Dominio Poro en Tándem , Canales de Potasio con Entrada de Voltaje , Animales , Humanos , Potenciales de Acción/fisiología , Potenciales de la Membrana/fisiología , Axones/fisiología , Potasio , MamíferosRESUMEN
Two pore domain potassium channels (K2P) are strongly expressed in the nervous system (CNS), where they play a central role in excitability. These channels give rise to background K+ currents, also known as IKSO (standing-outward potassium current). We detected the expression in primary cultured cerebellar granule neurons (CGNs) of TWIK-1 (K2P1), TASK-1 (K2P3), TASK-3 (K2P9), and TRESK (K2P18) channels by immunocytochemistry and their association with lipid rafts using the specific lipids raft markers flotillin-2 and caveolin-1. At the functional level, methyl-ß-cyclodextrin (MßCD, 5 mM) reduced IKSO currents by ~40% in CGN cells. To dissect out this effect, we heterologously expressed the human TWIK-1, TASK-1, TASK-3, and TRESK channels in HEK-293 cells. MßCD directly blocked TASK-1 and TASK-3 channels and the covalently concatenated heterodimer TASK-1/TASK-3 currents. Conversely, MßCD did not affect TWIK-1- and TRESK-mediated K+ currents. On the other hand, the cholesterol-depleting agent filipin III did not affect TASK-1/TASK-3 channels. Together, the results suggest that neuronal background K+ channels are associated to lipid raft environments whilst the functional activity is independent of the cholesterol membrane organization.
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The ability to sense pain signals is closely linked to the activity of ion channels expressed in nociceptors, the first neurons that transduce noxious stimuli into pain. Among these ion channels, TREK1, TREK2 and TRAAK from the TREK subfamily of the Two-Pore-Domain potassium (K2P) channels, are hyperpolarizing channels that render neurons hypoexcitable. They are regulated by diverse physical and chemical stimuli as well as neurotransmitters through G-protein coupled receptor activation. Here, we review the molecular mechanisms underlying these regulations and their functional relevance in pain and migraine induction.
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Trastornos Migrañosos , Canales de Potasio de Dominio Poro en Tándem , Humanos , Dolor , Percepción del Dolor , PotasioRESUMEN
TWIK-related spinal cord potassium (TRESK) and TWIK-related potassium (TREK) channels are both subfamilies of the two-pore domain potassium (K2P) channel group. Despite major structural, pharmacological, as well as biophysical differences, emerging data suggest that channels of these two subfamilies are functionally more closely related than previously assumed. Recent studies, for instance, indicate an assembling of TRESK and TREK subunits, leading to the formation of heterodimeric channels with different functional properties compared to homodimeric ones. Formation of tandems consisting of TRESK and TREK subunits might thus multiply the functional diversity of both TRESK and TREK activity. Based on the involvement of these channels in the pathophysiology of migraine, we here highlight the role as well as the impact of the interplay of TRESK and TREK subunits in the context of different disease settings. In this regard, we focus on their involvement in migraine and pain syndromes, as well as on their influence on (neuro-)inflammatory processes. Furthermore, we describe the potential implications for innovative therapeutic strategies that take advantage of TRESK and TREK modulation as well as obstacles encountered in the development of therapies related to the aforementioned diseases.
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Enfermedades Neuroinflamatorias/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio/metabolismo , Humanos , Canales de Potasio/química , Canales de Potasio/genética , Canales de Potasio de Dominio Poro en Tándem/química , Canales de Potasio de Dominio Poro en Tándem/genética , Multimerización de ProteínaRESUMEN
Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases. In the present study we investigated the effects of known K2P channel modulators on TWIK2 channel expressed in a heterologous system. In order to increase plasma membrane expression and thus TWIK2 currents, a mutant channel with three mutations (TWIK2I289A/L290A/Y308A) in the C-terminus was expressed in COS-7 cells. TWIK2 currents were assessed using whole-cell voltage-clamp recording. Among 6 known K2P channel modulators tested (DCPIB, quinine, fluoxetine, ML365, ML335, and TKDC), ML365 was the most potent TWIK2 channel blocker with an IC50 value of 4.07 ± 1.5 µM. Furthermore, ML365 selectively inhibited TWIK2 without affecting TWIK1 or THIK1 channels. We showed that ML365 (1, 5 µM) concentration-dependently inhibited ATP-induced NLRP3 inflammasome activation in LPS-primed murine BMDMs, whereas it did not affect nigericin-induced NLRP3, or non-canonical, AIM2 and NLRC4 inflammasomes activation. Knockdown of TWIK2 significantly impaired the inhibitory effect of ML365 on ATP-induced NLRP3 inflammasome activation. Moreover, we demonstrated that pre-administration of ML365 (1, 10, 25 mg/kg, ip) dose-dependently ameliorated LPS-induced endotoxic shock in mice. In a preliminary pharmacokinetic study conducted in rats, ML365 showed good absolute oral bioavailability with F value of 22.49%. In conclusion, ML365 provides a structural reference for future design of selective TWIK2 channel inhibitors in treating related inflammatory diseases.
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Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Adenosina Trifosfato/metabolismo , Animales , Proteínas de Unión al ADN , Inflamasomas/metabolismo , Inflamación , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , RatasRESUMEN
In myelinated nerve fibres, action potentials are generated at nodes of Ranvier. These structures are located at interruptions of the myelin sheath, forming narrow gaps with small rings of axolemma freely exposed to the extracellular space. The mammalian node contains a high density of Na+ channels and K+ -selective leakage channels. Voltage-dependent Kv1 channels are only present in the juxta-paranode. Recently, the leakage channels have been identified as K2P channels (TRAAK, TREK-1). K2P channels are K+ -selective 'background' channels, characterized by outward rectification and their ability to be activated, e.g. by temperature, mechanical stretch or arachidonic acid. We are only beginning to elucidate the peculiar functions of nodal K2P channels. I will discuss two functions of the nodal K2P-mediated conductance. First, at body temperature K2P channels have a high open probability, thereby inducing a resting potential of about -85 mV. This negative resting potential reduces steady-state Na+ channel inactivation and ensures a large Na+ inward current upon a depolarizing stimulus. Second, the K2P conductance is involved in nodal action potential repolarization. The identification of nodal K2P channels is exciting since it shows that the nodal K+ conductance is not a fixed value but can be changed: it can be increased or decreased by a broad range of K2P modulators, thereby modulating, for example, the resting potential. The functional importance of nodal K2P channels will be exemplified by describing in more detail the function of the K2P conductance increase by raising the temperature from room temperature to 37°C.
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Axones , Fibras Nerviosas Mielínicas , Potenciales de Acción , Animales , Potenciales de la Membrana , Vaina de MielinaRESUMEN
Astrocytes are key regulators of their surroundings by receiving and integrating stimuli from their local microenvironment, thereby regulating glial and neuronal homeostasis. Cumulating evidence supports a plethora of heterogenic astrocyte subpopulations that differ morphologically and in their expression patterns of receptors, transporters and ion channels, as well as in their functional specialisation. Astrocytic heterogeneity is especially relevant under pathological conditions. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), morphologically distinct astrocytic subtypes were identified and could be linked to transcriptome changes during different disease stages and regions. To allow for continuous awareness of changing stimuli across age and diseases, astrocytes are equipped with a variety of receptors and ion channels allowing the precise perception of environmental cues. Recent studies implicate the diverse repertoire of astrocytic ion channels - including transient receptor potential channels, voltage-gated calcium channels, inwardly rectifying K+ channels, and two-pore domain potassium channels - in sensing the brain state in physiology, inflammation and ischemia. Here, we review current evidence regarding astrocytic potassium and calcium channels and their functional contribution in homeostasis, neuroinflammation and stroke.
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Canales de Calcio , Potasio , Animales , Astrocitos , RatonesRESUMEN
Years before the first two-pore domain potassium channel (K2P) was cloned, certain ion channels had already been demonstrated to be present in the heart with characteristics and properties usually attributed to the TREK channels (a subfamily of K2P channels). K2P channels were later detected in cardiac tissue by RT-PCR, although the distribution of the different K2P subfamilies in the heart seems to depend on the species analyzed. In order to collect relevant information in this regard, we focus here on the TWIK, TASK and TREK cardiac channels, their putative roles in cardiac physiology and their implication in coronary pathologies. Most of the RNA expression data and electrophysiological recordings available to date support the presence of these different K2P subfamilies in distinct cardiac cells. Likewise, we show how these channels may be involved in certain pathologies, such as atrial fibrillation, long QT syndrome and Brugada syndrome.
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Miocardio/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Animales , Cardiopatías/metabolismo , HumanosRESUMEN
Pulmonary arterial hypertension (PAH) is an aggressive vascular remodeling disease that carries a high morbidity and mortality rate. Treprostinil (Remodulin) is a stable prostacyclin analogue with potent vasodilatory and anti-proliferative activity, approved by the FDA and WHO as a treatment for PAH. A limitation of this therapy is the severe subcutaneous site pain and other forms of pain experienced by some patients, which can lead to significant non-compliance. TWIK-related potassium channels (TREK-1 and TREK-2) are highly expressed in sensory neurons, where they play a role in regulating sensory neuron excitability. Downregulation, inhibition or mutation of these channels leads to enhanced pain sensitivity. Using whole-cell patch-clamp electrophysiological recordings, we show, for the first time, that treprostinil is a potent antagonist of human TREK-1 and TREK-2 channels but not of TASK-1 channels. An increase in TASK-1 channel current was observed with prolonged incubation, consistent with its therapeutic role in PAH. To investigate treprostinil-induced inhibition of TREK, site-directed mutagenesis of a number of amino acids, identified as important for the action of other regulatory compounds, was carried out. We found that a gain of function mutation of TREK-1 (Y284A) attenuated treprostinil inhibition, while a selective activator of TREK channels, BL-1249, overcame the inhibitory effect of treprostinil. Our data suggests that subcutaneous site pain experienced during treprostinil therapy may result from inhibition of TREK channels near the injection site and that pre-activation of these channels prior to treatment has the potential to alleviate this nociceptive activity.
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Glutamatergic and GABAergic synaptic transmission controls excitation and inhibition of postsynaptic neurons, whereas activity of ion channels modulates neuronal intrinsic excitability. However, it is unclear how excessive neuronal excitation affects intrinsic inhibition to regain homeostatic stability under physiological or pathophysiological conditions. Here, we report that a seizure-like sustained depolarization can induce short-term inhibition of hippocampal CA3 neurons via a mechanism of membrane shunting. This depolarization-induced shunting inhibition (DShI) mediates a non-synaptic, but neuronal intrinsic, short-term plasticity that is able to suppress action potential generation and postsynaptic responses by activated ionotropic receptors. We demonstrate that the TRESK channel significantly contributes to DShI. Disruption of DShI by genetic knockout of TRESK exacerbates the sensitivity and severity of epileptic seizures of mice, whereas overexpression of TRESK attenuates seizures. In summary, these results uncover a type of homeostatic intrinsic plasticity and its underlying mechanism. TRESK might represent a therapeutic target for antiepileptic drugs.
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Potenciales de Acción/fisiología , Canales de Potasio/metabolismo , Convulsiones/fisiopatología , Potenciales de Acción/efectos de los fármacos , Animales , Calcio/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Canales Iónicos/metabolismo , Ligandos , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio/deficiencia , Canales de Potasio/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Convulsiones/genética , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
K2P channel is the leaky potassium channel that is critical to keep up the negative resting membrane potential for legitimate electrical conductivity of the excitable tissues. Recently, many substances and medication elements are discovered that could either straightforwardly or in a roundabout way influence the 15 distinctive K+ ion channels including TWIK, TREK, TASK, TALK, THIK, and TRESK. Opening and shutting of these channels or any adjustment in their conduct is thought to alter the pathophysiological condition of CNS. There is no document available till now to explain in detail about the molecular mechanism of agents acting on K2P channel. Accordingly, in this review we cover the current research and mechanism of action of these channels, we have also tried to mention the detailed effect of drugs and how the channel behavior changes by focusing on recent advances regarding activation and modulation of ion channels.
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Enfermedades del Sistema Nervioso , Canales de Potasio de Dominio Poro en Tándem , Humanos , Potenciales de la Membrana , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Potasio/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genéticaRESUMEN
The family of two-pore domain potassium (K2P) channels is critically involved in central cellular functions such as ion homeostasis, cell development, and excitability. K2P channels are widely expressed in different human cell types and organs. It is therefore not surprising that aberrant expression and function of K2P channels are related to a spectrum of human diseases, including cancer, autoimmune, CNS, cardiovascular, and urinary tract disorders. Despite homologies in structure, expression, and stimulus, the functional diversity of K2P channels leads to heterogeneous influences on human diseases. The role of individual K2P channels in different disorders depends on expression patterns and modulation in cellular functions. However, an imbalance of potassium homeostasis and action potentials contributes to most disease pathologies. In this review, we provide an overview of current knowledge on the role of K2P channels in human diseases. We look at altered channel expression and function, the potential underlying molecular mechanisms, and prospective research directions in the field of K2P channels.
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Enfermedades Autoinmunes/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Gastrointestinales/metabolismo , Enfermedades Hematológicas/metabolismo , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Enfermedades Urológicas/metabolismo , Potenciales de Acción/fisiología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Expresión Génica , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/patología , Homeostasis/genética , Humanos , Transporte Iónico , Neoplasias/genética , Neoplasias/patología , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Especificidad de Órganos , Potasio/metabolismo , Canales de Potasio de Dominio Poro en Tándem/clasificación , Canales de Potasio de Dominio Poro en Tándem/genética , Isoformas de Proteínas/clasificación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Enfermedades Urológicas/genética , Enfermedades Urológicas/patologíaRESUMEN
Ligand-gated ion channels (LGICs) are natural biosensors generating electrical signals in response to the binding of specific ligands. Creating de novo LGICs for biosensing applications is technically challenging. We have previously designed modified LGICs by linking G protein-coupled receptors (GPCRs) to the Kir6.2 channel. In this article, we extrapolate these design concepts to other channels with different structures and oligomeric states, namely a tetrameric viral Kcv channel and the dimeric mouse TREK-1 channel. After precise engineering of the linker regions, the two ion channels were successfully regulated by a GPCR fused to their N-terminal domain. Two-electrode voltage-clamp recordings showed that Kcv and mTREK-1 fusions were inhibited and activated by GPCR agonists, respectively, and antagonists abolished both effects. Thus, dissimilar ion channels can be allosterically regulated through their N-terminal domains, suggesting that this is a generalizable approach for ion channel engineering.