scholarly journals Two-pore domain potassium channels (K2P) in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Austin M. Baggetta ◽  
Douglas A. Bayliss ◽  
Gábor Czirják ◽  
Péter Enyedi ◽  
Steve A.N. Goldstein ◽  
...  
Keyword(s):  
Single Channels ◽  
Primary Sequence ◽  
Α Subunit ◽  
Voltage Range ◽  
K Channels ◽  
Structural And Functional Properties ◽  
Conduction Pathway ◽  
K2p Channels ◽  
The Common ◽  
Pore Domain

The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two-pore domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

scholarly journals Two P domain potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Douglas A. Bayliss ◽  
Gábor Czirják ◽  
Péter Enyedi ◽  
Steve A.N. Goldstein ◽  
Florian Lesage ◽  
...  
Keyword(s):  
Single Channels ◽  
Primary Sequence ◽  
Α Subunit ◽  
Voltage Range ◽  
K Channels ◽  
Structural And Functional Properties ◽  
Conduction Pathway ◽  
K2p Channels ◽  
The Common ◽  
P Domain

The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

scholarly journals Two P domain potassium channels in GtoPdb v.2021.2

2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Austin M. Baggetta ◽  
Douglas A. Bayliss ◽  
Gábor Czirják ◽  
Péter Enyedi ◽  
Steve A.N. Goldstein ◽  
...  
Keyword(s):  
Single Channels ◽  
Primary Sequence ◽  
Α Subunit ◽  
Voltage Range ◽  
K Channels ◽  
Structural And Functional Properties ◽  
Conduction Pathway ◽  
K2p Channels ◽  
The Common ◽  
P Domain

The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage-range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore-forming α-subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K2P channels (and not two-pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the More detailed introduction, is based on similarities in both structural and functional properties within subfamilies and this explains the "common abbreviation" nomenclature in the tables below.

scholarly journals Batrachotoxin-activated Na+ channels in planar lipid bilayers. Competition of tetrodotoxin block by Na+.

1984 ◽  
Vol 84 (5) ◽  
pp. 665-686 ◽  
Author(s):  
E Moczydlowski ◽  
S S Garber ◽  
C Miller
Keyword(s):  
Lipid Bilayers ◽  
Membrane Vesicles ◽  
Receptor Site ◽  
Single Channels ◽  
Planar Lipid Bilayers ◽  
Na Channels ◽  
Plasma Membrane Vesicles ◽  
Voltage Range ◽  
Conduction Pathway ◽  
Almost All

Single Na+ channels from rat skeletal muscle plasma membrane vesicles were inserted into planar lipid bilayers formed from neutral phospholipids and were observed in the presence of batrachotoxin. The batrachotoxin-modified channel activates in the voltage range -120 to -80 mV and remains open almost all the time at voltages positive to -60 mV. Low levels of tetrodotoxin (TTX) induce slow fluctuations of channel current, which represent the binding and dissociation of single TTX molecules to single channels. The rates of association and dissociation of TTX are both voltage dependent, and the association rate is competitively inhibited by Na+. This inhibition is observed only when Na+ is increased on the TTX binding side of the channel. The results suggest that the TTX receptor site is located at the channel's outer mouth, and that the Na+ competition site is not located deeply within the channel's conduction pathway.

scholarly journals Polymodal activation of the TREK-2 K2P channel produces structurally distinct open states

2016 ◽  
Vol 147 (6) ◽  
pp. 497-505 ◽  
Author(s):  
Conor McClenaghan ◽  
Marcus Schewe ◽  
Prafulla Aryal ◽  
Elisabeth P. Carpenter ◽  
Thomas Baukrowitz ◽  
...  
Keyword(s):  
Channel Activation ◽  
K Channels ◽  
State Dependent ◽  
Wide Range ◽  
K2p Channels ◽  
Chemical Stimuli ◽  
Structural Mechanisms ◽  
Open States ◽  
Pore Domain ◽  
Physical And Chemical

The TREK subfamily of two-pore domain (K2P) K+ channels exhibit polymodal gating by a wide range of physical and chemical stimuli. Crystal structures now exist for these channels in two main states referred to as the “up” and “down” conformations. However, recent studies have resulted in contradictory and mutually exclusive conclusions about the functional (i.e., conductive) status of these two conformations. To address this problem, we have used the state-dependent TREK-2 inhibitor norfluoxetine that can only bind to the down state, thereby allowing us to distinguish between these two conformations when activated by different stimuli. Our results reconcile these previously contradictory gating models by demonstrating that activation by pressure, temperature, voltage, and pH produce more than one structurally distinct open state and reveal that channel activation does not simply involve switching between the up and down conformations. These results also highlight the diversity of structural mechanisms that K2P channels use to integrate polymodal gating signals.

scholarly journals The Insensitivity of TASK-3 K2P Channels to External Tetraethylammonium (TEA) Partially Depends on the Cap Structure

2018 ◽  
Vol 19 (8) ◽  
pp. 2437 ◽  
Author(s):  
Guierdy Concha ◽  
Daniel Bustos ◽  
Rafael Zúñiga ◽  
Marcelo Catalán ◽  
Leandro Zúñiga
Keyword(s):  
Functional Role ◽  
Simulation Analysis ◽  
K Channel ◽  
Channel Blockers ◽  
Tyrosine Residue ◽  
K Channels ◽  
Enhanced Sensitivity ◽  
K2p Channels ◽  
Pore Domain

Two-pore domain K+ channels (K2P) display a characteristic extracellular cap structure formed by two M1-P1 linkers, the functional role of which is poorly understood. It has been proposed that the presence of the cap explains the insensitivity of K2P channels to several K+ channel blockers including tetraethylammonium (TEA). We have explored this hypothesis using mutagenesis and functional analysis, followed by molecular simulations. Our results show that the deletion of the cap structure of TASK-3 (TWIK-related acid-sensitive K+ channel) generates a TEA-sensitive channel with an IC50 of 11.8 ± 0.4 mM. The enhanced sensitivity to TEA displayed by the cap-less channel is also explained by the presence of an extra tyrosine residue at position 99. These results were corroborated by molecular simulation analysis, which shows an increased stability in the binding of TEA to the cap-less channel when a ring of four tyrosine is present at the external entrance of the permeation pathway. Consistently, Y99A or Y205A single-residue mutants generated in a cap-less channel backbone resulted in TASK-3 channels with low affinity to external TEA.

scholarly journals A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

2020 ◽  
pp. 247255522097612
Author(s):  
David McCoull ◽  
Emma Ococks ◽  
Jonathan M. Large ◽  
David C. Tickle ◽  
Alistair Mathie ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Point Of View ◽  
Resting Membrane Potential ◽  
Small Molecule Activation ◽  
Target Class ◽  
Index Set ◽  
Diverse Range ◽  
K2p Channels ◽  
Additional Approach ◽  
Pore Domain

Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a “target class” approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration–response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

scholarly journals Acute Oxygen Sensing in Heme Oxygenase-2 Null Mice

2006 ◽  
Vol 128 (4) ◽  
pp. 405-411 ◽  
Author(s):  
Patricia Ortega-Sáenz ◽  
Alberto Pascual ◽  
Raquel Gómez-Díaz ◽  
José López-Barneo
Keyword(s):  
Gene Expression ◽  
K Channel ◽  
Α Subunit ◽  
Organ Growth ◽  
K Channels ◽  
Channel Gene ◽  
Sensitive Organ ◽  
Stress Dependent ◽  
Acute Oxygen Sensing ◽  
O2 Sensing

Hemeoxygenase-2 (HO-2) is an antioxidant enzyme that can modulate recombinant maxi-K+ channels and has been proposed to be the acute O2 sensor in the carotid body (CB). We have tested the physiological contribution of this enzyme to O2 sensing using HO-2 null mice. HO-2 deficiency leads to a CB phenotype characterized by organ growth and alteration in the expression of stress-dependent genes, including the maxi-K+ channel α-subunit. However, sensitivity to hypoxia of CB is remarkably similar in HO-2 null animals and their control littermates. Moreover, the response to hypoxia in mouse and rat CB cells was maintained after blockade of maxi-K+ channels with iberiotoxin. Hypoxia responsiveness of the adrenal medulla (AM) (another acutely responding O2-sensitive organ) was also unaltered by HO-2 deficiency. Our data suggest that redox disregulation resulting from HO-2 deficiency affects maxi-K+ channel gene expression but it does not alter the intrinsic O2 sensitivity of CB or AM cells. Therefore, HO-2 is not a universally used acute O2 sensor.

scholarly journals Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium

Reproduction ◽  
2005 ◽  
Vol 129 (4) ◽  
pp. 525-530 ◽  
Author(s):  
Xilian Bai ◽  
George J Bugg ◽  
Susan L Greenwood ◽  
Jocelyn D Glazier ◽  
Colin P Sibley ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Pregnant Women ◽  
Human Myometrium ◽  
Rt Pcr ◽  
Excitable Cells ◽  
K Channels ◽  
Myometrial Cells ◽  
Channel Proteins ◽  
A Site ◽  
Pore Domain

Two-pore domain K+channels are an emerging family of K+channels that may contribute to setting membrane potential in both electrically excitable and non-excitable cells and, as such, influence cellular function. The human uteroplacental unit contains both excitable (e.g. myometrial) and non-excitable cells, whose function depends upon the activity of K+channels. We have therefore investigated the expression of two members of this family, TWIK (two-pore domain weak inward rectifying K+channel)-related acid-sensitive K+channel (TASK) and TWIK-related K+channel (TREK) in human myometrium. Using RT-PCR the mRNA expression of TASK and TREK isoforms was examined in myometrial tissue from pregnant women. mRNAs encoding TASK1, 4 and 5 and TREK1 were detected whereas weak or no signals were observed for TASK2, TASK3 and TREK2. Western blotting for TASK1 gave two bands of approximately 44 and 65 kDa, whereas TREK1 gave bands of approximately 59 and 90 kDa in myometrium from pregnant women. TASK1 and TREK1 immunofluorescence was prominent in intracellular and plasmalemmal locations within myometrial cells. Therefore, we conclude that the human myometrium is a site of expression for the two-pore domain K+channel proteins TASK1 and TREK1.

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