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Article ; Online: N-terminal tetrapeptide T/SPLH motifs contribute to multimodal activation of human TRPA1 channel.

Hynkova, Anna / Marsakova, Lenka / Vaskova, Jana / Vlachova, Viktorie

2016 Volume 6, Page(s) 28700

Abstract: Human transient receptor potential ankyrin channel 1 (TRPA1) is a polymodal sensor implicated in pain, inflammation and itching. An important locus for TRPA1 regulation is the cytoplasmic N-terminal domain, through which various exogenous electrophilic ... ...

Abstract	Human transient receptor potential ankyrin channel 1 (TRPA1) is a polymodal sensor implicated in pain, inflammation and itching. An important locus for TRPA1 regulation is the cytoplasmic N-terminal domain, through which various exogenous electrophilic compounds such as allyl-isothiocyanate from mustard oil or cinnamaldehyde from cinnamon activate primary afferent nociceptors. This major region is comprised of a tandem set of 17 ankyrin repeats (AR1-AR17), five of them contain a strictly conserved T/SPLH tetrapeptide motif, a hallmark of an important and evolutionarily conserved contribution to conformational stability. Here, we characterize the functional consequences of putatively stabilizing and destabilizing mutations in these important structural units and identify AR2, AR6, and AR11-13 to be distinctly involved in the allosteric activation of TRPA1 by chemical irritants, cytoplasmic calcium, and membrane voltage. Considering the potential involvement of the T/SP motifs as putative phosphorylation sites, we also show that proline-directed Ser/Thr kinase CDK5 modulates the activity of TRPA1, and that T673 outside the AR-domain is its only possible target. Our data suggest that the most strictly conserved N-terminal ARs define the energetics of the TRPA1 channel gate and contribute to chemical-, calcium- and voltage-dependence.
Language	English
Publishing date	2016-06-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep28700
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Article: The First Extracellular Linker Is Important for Several Aspects of the Gating Mechanism of Human TRPA1 Channel.

Marsakova, Lenka / Barvik, Ivan / Zima, Vlastimil / Zimova, Lucie / Vlachova, Viktorie

Frontiers in molecular neuroscience

2017 Volume 10, Page(s) 16

Abstract: Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel involved in pain, inflammation and itching. This channel gates in response to many irritant and proalgesic agents, and can be modulated by calcium and depolarizing voltage. While ...

Abstract	Transient receptor potential ankyrin 1 (TRPA1) is an excitatory ion channel involved in pain, inflammation and itching. This channel gates in response to many irritant and proalgesic agents, and can be modulated by calcium and depolarizing voltage. While the closed-state structure of TRPA1 has been recently resolved, also having its open state is essential for understanding how this channel works. Here we use molecular dynamics simulations combined with electrophysiological measurements and systematic mutagenesis to predict and explore the conformational changes coupled to the expansion of the presumptive channel's lower gate. We show that, upon opening, the upper part of the sensor module approaches the pore domain of an adjacent subunit and the conformational dynamics of the first extracellular flexible loop may govern the voltage-dependence of multimodal gating, thereby serving to stabilize the open state of the channel. These results are generally important in understanding the structure and function of TRPA1 and offer new insights into the gating mechanism of TRPA1 and related channels.
Language	English
Publishing date	2017-01-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2017.00016
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Article ; Online: Pore helix domain is critical to camphor sensitivity of transient receptor potential vanilloid 1 channel.

Marsakova, Lenka / Touska, Filip / Krusek, Jan / Vlachova, Viktorie

Anesthesiology

2012 Volume 116, Issue 4, Page(s) 903–917

Abstract: Background: The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new ... ...

Abstract	Background: The recent discovery that camphor activates and strongly desensitizes the capsaicin-sensitive and noxious heat-sensitive channel transient receptor potential vanilloid subfamily member 1 (TRPV1) has provided new insights and opened up new research paths toward understanding why this naturally occurring monoterpene is widely used in human medicine for its local counter-irritant, antipruritic, and anesthetic properties. However, the molecular basis for camphor sensitivity remains mostly unknown. The authors attempt to explore the nature of the activation pathways evoked by camphor and narrow down a putative interaction site at TRPV1. Methods: The authors transiently expressed wild-type or specifically mutated recombinant TRPV1 channels in human embryonic kidney cells HEK293T and recorded cation currents with the whole cell, patch clamp technique. To monitor changes in the spatial distribution of phosphatidylinositol 4,5-bisphosphate, they used fluorescence resonance energy transfer measurements from cells transfected with the fluorescent protein-tagged pleckstrin homology domains of phospholipase C. Results: The results revealed that camphor modulates TRPV1 channel through the outer pore helix domain by affecting its overall gating equilibrium. In addition, camphor, which generally is known to decrease the fluidity of cell plasma membranes, may also regulate the activity of TRPV1 by inducing changes in the spatial distribution of phosphatidylinositol-4,5-bisphosphate on the inner leaflet of the plasma membrane. Conclusions: The findings of this study provide novel insights into the structural basis for the modulation of TRPV1 channel by camphor and may provide an explanation for the mechanism by which camphor modulates thermal sensation in vivo.
MeSH term(s)	Animals ; Binding Sites/drug effects ; Binding Sites/physiology ; Camphor/chemistry ; Camphor/pharmacology ; HEK293 Cells ; Humans ; Ion Channel Gating/drug effects ; Ion Channel Gating/physiology ; Nuclear Pore/drug effects ; Nuclear Pore/metabolism ; Protein Structure, Tertiary/drug effects ; Protein Structure, Tertiary/physiology ; Rats ; TRPV Cation Channels/antagonists & inhibitors ; TRPV Cation Channels/chemistry ; TRPV Cation Channels/physiology
Chemical Substances	TRPV Cation Channels ; TRPV1 protein, human ; Camphor (76-22-2)
Language	English
Publishing date	2012-04
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	269-0
ISSN	1528-1175 ; 0003-3022
ISSN (online)	1528-1175
ISSN	0003-3022
DOI	10.1097/ALN.0b013e318249cf62
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Article ; Online: A "cute" desensitization of TRPV1.

Touska, Filip / Marsakova, Lenka / Teisinger, Jan / Vlachova, Viktorie

Current pharmaceutical biotechnology

2010 Volume 12, Issue 1, Page(s) 122–129

Abstract: Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization ...

Abstract	Capsaicin and other vanilloids selectively excite and subsequently desensitize pain-conducting nerve fibers (nociceptors) and this process contributes to the analgesic (and thus therapeutically relevant) effects of these compounds. Such a desensitization process is triggered by the activation of the transient receptor potential vanilloid subtype 1 receptor channels (TRPV1) that open their cationic pores, permeable to sodium, potassium and calcium (Ca(2+)) ions. Depending on the duration of capsaicin exposure and the external calcium concentration, the Ca(2+) influx via TRPV1 channels desensitizes the channels themselves, which, from the cellular point of view, represents a feedback mechanism protecting the nociceptive neuron from toxic Ca(2+) overload. The 'acute desensitization' accounts for most of the reduction in responsiveness occurring within the first few (~20) seconds after the vanilloids are administered to the cell for the first time. Another form of desensitization is 'tachyphylaxis', which is a reduction in the response to repeated applications of vanilloid. The wealth of pathways following TRPV1 activation that lead to increased intracellular Ca(2+) levels and both forms of desensitization is huge and they might utilise just about every known type of signalling molecule. This review will not attempt to cover all historical aspects of research into all these processes. Instead, it will try to highlight some new challenging thoughts on the important phenomenon of TRPV1 desensitization and will focus on the putative mechanisms that are thought to account for the acute phase of this process.
MeSH term(s)	Analgesics/metabolism ; Analgesics/pharmacology ; Animals ; Calcium/metabolism ; Capsaicin/metabolism ; Capsaicin/pharmacology ; Humans ; Nociceptors/metabolism ; Phosphoinositide Phospholipase C/metabolism ; Phosphorylation ; TRPV Cation Channels/agonists ; TRPV Cation Channels/metabolism
Chemical Substances	Analgesics ; TRPV Cation Channels ; TRPV1 protein, human ; Phosphoinositide Phospholipase C (EC 3.1.4.11) ; Capsaicin (S07O44R1ZM) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2010-09-18
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2132197-8
ISSN	1873-4316 ; 1389-2010
ISSN (online)	1873-4316
ISSN	1389-2010
DOI	10.2174/138920111793937826
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Article ; Online: Conserved residues within the putative S4-S5 region serve distinct functions among thermosensitive vanilloid transient receptor potential (TRPV) channels.

Boukalova, Stepana / Marsakova, Lenka / Teisinger, Jan / Vlachova, Viktorie

The Journal of biological chemistry

2010 Volume 285, Issue 53, Page(s) 41455–41462

Abstract: The vanilloid transient receptor potential channel TRPV1 is a tetrameric six-transmembrane segment (S1-S6) channel that can be synergistically activated by various proalgesic agents such as capsaicin, protons, heat, or highly depolarizing voltages, and ... ...

Abstract	The vanilloid transient receptor potential channel TRPV1 is a tetrameric six-transmembrane segment (S1-S6) channel that can be synergistically activated by various proalgesic agents such as capsaicin, protons, heat, or highly depolarizing voltages, and also by 2-aminoethoxydiphenyl borate (2-APB), a common activator of the related thermally gated vanilloid TRP channels TRPV1, TRPV2, and TRPV3. In these channels, the conserved charged residues in the intracellular S4-S5 region have been proposed to constitute part of a voltage sensor that acts in concert with other stimuli to regulate channel activation. The molecular basis of this gating event is poorly understood. We mutated charged residues all along the S4 and the S4-S5 linker of TRPV1 and identified four potential voltage-sensing residues (Arg(557), Glu(570), Asp(576), and Arg(579)) that, when specifically mutated, altered the functionality of the channel with respect to voltage, capsaicin, heat, 2-APB, and/or their interactions in different ways. The nonfunctional charge-reversing mutations R557E and R579E were partially rescued by the charge-swapping mutations R557E/E570R and D576R/R579E, indicating that electrostatic interactions contribute to allosteric coupling between the voltage-, temperature- and capsaicin-dependent activation mechanisms. The mutant K571E was normal in all aspects of TRPV1 activation except for 2-APB, revealing the specific role of Lys(571) in chemical sensitivity. Surprisingly, substitutions at homologous residues in TRPV2 or TRPV3 had no effect on temperature- and 2-APB-induced activity. Thus, the charged residues in S4 and the S4-S5 linker contribute to voltage sensing in TRPV1 and, despite their highly conserved nature, regulate the temperature and chemical gating in the various TRPV channels in different ways.
MeSH term(s)	Amino Acid Sequence ; Electrophysiology/methods ; Hot Temperature ; Humans ; Ion Channels/chemistry ; Membrane Proteins/chemistry ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Mutation ; Protein Structure, Tertiary ; Sequence Analysis, DNA ; Sequence Homology, Amino Acid ; Structure-Activity Relationship ; TRPV Cation Channels/metabolism ; Transient Receptor Potential Channels/metabolism
Chemical Substances	Ion Channels ; Membrane Proteins ; TRPV Cation Channels ; Transient Receptor Potential Channels
Language	English
Publishing date	2010-11-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M110.145466
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Article ; Online: C-terminal acidic cluster is involved in Ca2+-induced regulation of human transient receptor potential ankyrin 1 channel.

Sura, Lucie / Zíma, Vlastimil / Marsakova, Lenka / Hynkova, Anna / Barvík, Ivan / Vlachova, Viktorie

The Journal of biological chemistry

2012 Volume 287, Issue 22, Page(s) 18067–18077

Abstract: The transient receptor potential ankyrin 1 (TRPA1) channel is a Ca(2+)-permeable cation channel whose activation results from a complex synergy between distinct activation sites, one of which is especially important for determining its sensitivity to ... ...

Abstract	The transient receptor potential ankyrin 1 (TRPA1) channel is a Ca(2+)-permeable cation channel whose activation results from a complex synergy between distinct activation sites, one of which is especially important for determining its sensitivity to chemical, voltage and cold stimuli. From the cytoplasmic side, TRPA1 is critically regulated by Ca(2+) ions, and this mechanism represents a self-modulating feedback loop that first augments and then inhibits the initial activation. We investigated the contribution of the cluster of acidic residues in the distal C terminus of TRPA1 in these processes using mutagenesis, whole cell electrophysiology, and molecular dynamics simulations and found that the neutralization of four conserved residues, namely Glu(1077) and Asp(1080)-Asp(1082) in human TRPA1, had strong effects on the Ca(2+)- and voltage-dependent potentiation and/or inactivation of agonist-induced responses. The surprising finding was that truncation of the C terminus by only 20 residues selectively slowed down the Ca(2+)-dependent inactivation 2.9-fold without affecting other functional parameters. Our findings identify the conserved acidic motif in the C terminus that is actively involved in TRPA1 regulation by Ca(2+).
MeSH term(s)	Amino Acid Sequence ; Animals ; Calcium/metabolism ; Calcium Channels/chemistry ; Calcium Channels/metabolism ; Calcium Channels/physiology ; Cell Line ; Humans ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Mutation ; Nerve Tissue Proteins/chemistry ; Nerve Tissue Proteins/metabolism ; Nerve Tissue Proteins/physiology ; Sequence Homology, Amino Acid ; TRPA1 Cation Channel ; Transient Receptor Potential Channels/chemistry ; Transient Receptor Potential Channels/metabolism ; Transient Receptor Potential Channels/physiology
Chemical Substances	Calcium Channels ; Nerve Tissue Proteins ; TRPA1 Cation Channel ; TRPA1 protein, human ; Transient Receptor Potential Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M112.341859
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Article: Conserved Residues within the Putative S4-S5 Region Serve Distinct Functions among Thermosensitive Vanilloid Transient Receptor Potential (TRPV) Channels

Boukalova, Stepana / Marsakova, Lenka / Teisinger, Jan / Vlachova, Viktorie

Journal of biological chemistry. 2010 Dec. 31, v. 285, no. 53

2010

Abstract	The vanilloid transient receptor potential channel TRPV1 is a tetrameric six-transmembrane segment (S1-S6) channel that can be synergistically activated by various proalgesic agents such as capsaicin, protons, heat, or highly depolarizing voltages, and also by 2-aminoethoxydiphenyl borate (2-APB), a common activator of the related thermally gated vanilloid TRP channels TRPV1, TRPV2, and TRPV3. In these channels, the conserved charged residues in the intracellular S4-S5 region have been proposed to constitute part of a voltage sensor that acts in concert with other stimuli to regulate channel activation. The molecular basis of this gating event is poorly understood. We mutated charged residues all along the S4 and the S4-S5 linker of TRPV1 and identified four potential voltage-sensing residues (Arg⁵⁵⁷, Glu⁵⁷⁰, Asp⁵⁷⁶, and Arg⁵⁷⁹) that, when specifically mutated, altered the functionality of the channel with respect to voltage, capsaicin, heat, 2-APB, and/or their interactions in different ways. The nonfunctional charge-reversing mutations R557E and R579E were partially rescued by the charge-swapping mutations R557E/E570R and D576R/R579E, indicating that electrostatic interactions contribute to allosteric coupling between the voltage-, temperature- and capsaicin-dependent activation mechanisms. The mutant K571E was normal in all aspects of TRPV1 activation except for 2-APB, revealing the specific role of Lys⁵⁷¹ in chemical sensitivity. Surprisingly, substitutions at homologous residues in TRPV2 or TRPV3 had no effect on temperature- and 2-APB-induced activity. Thus, the charged residues in S4 and the S4-S5 linker contribute to voltage sensing in TRPV1 and, despite their highly conserved nature, regulate the temperature and chemical gating in the various TRPV channels in different ways.
Language	English
Dates of publication	2010-1231
Size	p. 41455-41462.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Superoxide dismutase and nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase polymorphisms and pancreatic cancer risk.

Mohelnikova-Duchonova, Beatrice / Marsakova, Lenka / Vrana, David / Holcatova, Ivana / Ryska, Miroslav / Smerhovsky, Zdenek / Slamova, Alena / Schejbalova, Miriam / Soucek, Pavel

Pancreas

2011 Volume 40, Issue 1, Page(s) 72–78

Abstract: Objectives: Pancreatic carcinoma etiology and molecular pathogenesis is weakly understood. According to the assumption that genetic variation in carcinogen metabolism further modifies the risk of exposure-related cancers, an association of functional ... ...

Abstract	Objectives: Pancreatic carcinoma etiology and molecular pathogenesis is weakly understood. According to the assumption that genetic variation in carcinogen metabolism further modifies the risk of exposure-related cancers, an association of functional polymorphisms in oxidative stress-modifying genes superoxide dismutase 2 (SOD2 [Ala16Val, rs4880]), SOD3 (Arg231Gly, rs1799895), nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase (NQO1 [Pro187Ser, rs1800566], and NQO2 (Phe47Leu, rs1143684) with pancreatic cancer risk was studied. Methods: Polymorphisms were studied by allelic discrimination. Results: In a hospital-based case-control study on 500 individuals (235 cases and 265 controls) of Czech white origin, SOD2, SOD3, NQO1, and NQO2 polymorphisms showed no significant association with pancreatic cancer risk. Major lifestyle factors such as smoking and alcohol, coffee, or tea consumption did not modify the effect of the studied polymorphisms. Conclusions: The first European study of the SOD2, SOD3, NQO1, and NQO2 roles in pancreatic cancer etiology did not find significant associations. Despite this observation, other populations with different lifestyle(s) may be at risk and should be further studied.
MeSH term(s)	Adult ; Aged ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; NAD(P)H Dehydrogenase (Quinone)/genetics ; Pancreatic Neoplasms/etiology ; Pancreatic Neoplasms/genetics ; Polymorphism, Genetic ; Quinone Reductases/genetics ; Risk Factors ; Superoxide Dismutase/genetics
Chemical Substances	SOD3 protein, human (EC 1.15.1.1) ; Superoxide Dismutase (EC 1.15.1.1) ; superoxide dismutase 2 (EC 1.15.1.1) ; NAD(P)H Dehydrogenase (Quinone) (EC 1.6.5.2) ; NQO1 protein, human (EC 1.6.5.2) ; NRH - quinone oxidoreductase2 (EC 1.6.99.-) ; Quinone Reductases (EC 1.6.99.-)
Language	English
Publishing date	2011-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632831-3
ISSN	1536-4828 ; 0885-3177
ISSN (online)	1536-4828
ISSN	0885-3177
DOI	10.1097/MPA.0b013e3181f74ad7
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