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1.
Proc Natl Acad Sci U S A ; 121(27): e2403333121, 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38923985

ABSTRACT

The transient receptor potential melastatin (TRPM) tetrameric cation channels are involved in a wide range of biological functions, from temperature sensing and taste transduction to regulation of cardiac function, inflammatory pain, and insulin secretion. The structurally conserved TRPM cytoplasmic domains make up >70 % of the total protein. To investigate the mechanism by which the TRPM cytoplasmic domains contribute to gating, we employed electrophysiology and cryo-EM to study TRPM5-a channel that primarily relies on activation via intracellular Ca2+. Here, we show that activation of mammalian TRPM5 channels is strongly altered by Ca2+-dependent desensitization. Structures of rat TRPM5 identify a series of conformational transitions triggered by Ca2+ binding, whereby formation and dissolution of cytoplasmic interprotomer interfaces appear to control activation and desensitization of the channel. This study shows the importance of the cytoplasmic assembly in TRPM5 channel function and sets the stage for future investigations of other members of the TRPM family.


Subject(s)
Calcium , Ion Channel Gating , TRPM Cation Channels , TRPM Cation Channels/metabolism , TRPM Cation Channels/chemistry , Animals , Ion Channel Gating/physiology , Rats , Calcium/metabolism , Humans , Cryoelectron Microscopy , HEK293 Cells , Cytosol/metabolism , Protein Domains , Protein Conformation
2.
Cell Calcium ; 119: 102874, 2024 May.
Article in English | MEDLINE | ID: mdl-38518427

ABSTRACT

Ruthenium red (RR) is a widely used inhibitor of Transient Receptor Potential (TRP) cation channels and other types of ion channels. Although RR has been generally accepted to inhibit TRP channels by physically blocking the ion permeation pathway, recent structural evidence suggests that it might also function as an antagonist, inducing conformational changes in the channel upon binding that result in closure of the pore. In a recent manuscript published in EMBO Reports, Ruth A. Pumroy and collaborators solve structures of TRPV2 and TRPV5 channels in the presence and absence of activators and RR. The data sheds light on the mechanism of inhibition by RR, while also opening new questions for further investigation.


Subject(s)
TRPV Cation Channels , Transient Receptor Potential Channels , Ruthenium Red/pharmacology , Ruthenium Red/metabolism , TRPV Cation Channels/metabolism
3.
Proc Natl Acad Sci U S A ; 120(24): e2301528120, 2023 06 13.
Article in English | MEDLINE | ID: mdl-37279277

ABSTRACT

Temperature influences dynamics and state-equilibrium distributions in all molecular processes, and only a relatively narrow range of temperatures is compatible with life-organisms must avoid temperature extremes that can cause physical damage or metabolic disruption. Animals evolved a set of sensory ion channels, many of them in the family of transient receptor potential cation channels that detect biologically relevant changes in temperature with remarkable sensitivity. Depending on the specific ion channel, heating or cooling elicits conformational changes in the channel to enable the flow of cations into sensory neurons, giving rise to electrical signaling and sensory perception. The molecular mechanisms responsible for the heightened temperature-sensitivity in these ion channels, as well as the molecular adaptations that make each channel specifically heat- or cold-activated, are largely unknown. It has been hypothesized that a heat capacity difference (ΔCp) between two conformational states of these biological thermosensors can drive their temperature-sensitivity, but no experimental measurements of ΔCp have been achieved for these channel proteins. Contrary to the general assumption that the ΔCp is constant, measurements from soluble proteins indicate that the ΔCp is likely to be a function of temperature. By investigating the theoretical consequences for a linearly temperature-dependent ΔCp on the open-closed equilibrium of an ion channel, we uncover a range of possible channel behaviors that are consistent with experimental measurements of channel activity and that extend beyond what had been generally assumed to be possible for a simple two-state model, challenging long-held assumptions about ion channel gating models at equilibrium.


Subject(s)
Hot Temperature , Transient Receptor Potential Channels , Animals , Temperature , Ion Channels/metabolism , Ion Channel Gating , Cold Temperature , Transient Receptor Potential Channels/metabolism
4.
Elife ; 122023 05 18.
Article in English | MEDLINE | ID: mdl-37199723

ABSTRACT

The cation-permeable TRPV2 channel is important for cardiac and immune cell function. Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique, we discover that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2-APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40°C) heat. Using cryo-EM, we uncover a new small-molecule binding site in the pore domain of rTRPV2 in addition to a nearby CBD site that had already been reported. The TRPV1 and TRPV3 channels are also activated by 2-APB and CBD and share multiple conserved features with TRPV2, but we find that strong sensitization by CBD is only observed in TRPV3, while sensitization for TRPV1 is much weaker. Mutations at non-conserved positions between rTRPV2 and rTRPV1 in either the pore domain or the CBD sites failed to confer strong sensitization by CBD in mutant rTRPV1 channels. Together, our results indicate that CBD-dependent sensitization of rTRPV2 channels engages multiple channel regions, and that the difference in sensitization strength between rTRPV2 and rTRPV1 channels does not originate from amino acid sequence differences at the CBD binding site or the pore domain. The remarkably robust effect of CBD on TRPV2 and TRPV3 channels offers a promising new tool to both understand and overcome one of the major roadblocks in the study of these channels - their resilience to activation.


Subject(s)
Cannabidiol , Cannabinoids , Rats , Animals , Cannabidiol/pharmacology , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Hot Temperature , Mutation
5.
bioRxiv ; 2023 Jan 27.
Article in English | MEDLINE | ID: mdl-36747846

ABSTRACT

The cation-permeable TRPV2 channel is essential for cardiac and immune cells. Cannabidiol (CBD), a non-psychoactive cannabinoid of clinical relevance, is one of the few molecules known to activate TRPV2. Using the patch-clamp technique we discover that CBD can sensitize current responses of the rat TRPV2 channel to the synthetic agonist 2-aminoethoxydiphenyl borate (2- APB) by over two orders of magnitude, without sensitizing channels to activation by moderate (40 °C) heat. Using cryo-EM we uncover a new small-molecule binding site in the pore domain of rTRPV2 that can be occupied by CBD in addition to a nearby CBD site that had already been reported. The TRPV1 and TRPV3 channels share >40% sequence identity with TRPV2 are also activated by 2-APB and CBD, but we only find a strong sensitizing effect of CBD on the response of mouse TRPV3 to 2-APB. Mutations at non-conserved positions between rTRPV2 and rTRPV1 in either the pore domain or the CBD sites failed to confer strong sensitization by CBD in mutant rTRPV1 channels. Together, our results indicate that CBD-dependent sensitization of TRPV2 channels engages multiple channel regions and possibly involves more than one CBD and 2-APB sites. The remarkably robust effect of CBD on TRPV2 and TRPV3 channels offers a promising new tool to both understand and overcome one of the major roadblocks in the study of these channels - their resilience to activation.

6.
Elife ; 92020 08 17.
Article in English | MEDLINE | ID: mdl-32804077

ABSTRACT

The recent proliferation of published TRP channel structures provides a foundation for understanding the diverse functional properties of this important family of ion channel proteins. To facilitate mechanistic investigations, we constructed a structure-based alignment of the transmembrane domains of 120 TRP channel structures. Comparison of structures determined in the absence or presence of activating stimuli reveals similar constrictions in the central ion permeation pathway near the intracellular end of the S6 helices, pointing to a conserved cytoplasmic gate and suggesting that most available structures represent non-conducting states. Comparison of the ion selectivity filters toward the extracellular end of the pore supports existing hypotheses for mechanisms of ion selectivity. Also conserved to varying extents are hot spots for interactions with hydrophobic ligands, lipids and ions, as well as discrete alterations in helix conformations. This analysis therefore provides a framework for investigating the structural basis of TRP channel gating mechanisms and pharmacology, and, despite the large number of structures included, reveals the need for additional structural data and for more functional studies to establish the mechanistic basis of TRP channel function.


Subject(s)
Transient Receptor Potential Channels/chemistry , Transient Receptor Potential Channels/physiology , Animals , Humans , Ion Channel Gating , Models, Molecular , Protein Conformation , Protein Domains , Sequence Alignment , Structure-Activity Relationship
7.
Elife ; 82019 11 14.
Article in English | MEDLINE | ID: mdl-31724952

ABSTRACT

Activation of TRPV1 channels in sensory neurons results in opening of a cation permeation pathway that triggers the sensation of pain. Opening of TRPV1 has been proposed to involve two gates that appear to prevent ion permeation in the absence of activators: the ion selectivity filter on the external side of the pore and the S6 helices that line the cytosolic half of the pore. Here we measured the access of thiol-reactive ions across the selectivity filters in rodent TRPV1-3 channels. Although our results are consistent with structural evidence that the selectivity filters in these channels are dynamic, they demonstrate that cations can permeate the ion selectivity filters even when channels are closed. Our results suggest that the selectivity filters in TRPV1-3 channels do not function as activation gates but might contribute to coupling structural rearrangements in the external pore to those in the cytosolic S6 gate.


Subject(s)
Ion Channel Gating , TRPV Cation Channels/metabolism , Animals , Cations/pharmacology , HEK293 Cells , Humans , Ion Channel Gating/drug effects , Ions , Mice , Rats , Silver/pharmacology
8.
Elife ; 82019 01 15.
Article in English | MEDLINE | ID: mdl-30644819

ABSTRACT

The Transient Receptor Potential Vanilloid 1 (TRPV) channel is activated by an array of stimuli, including heat and vanilloid compounds. The TRPV1 homologues TRPV2 and TRPV3 are also activated by heat, but sensitivity to vanilloids and many other agonists is not conserved among TRPV subfamily members. It was recently discovered that four mutations in TRPV2 are sufficient to render the channel sensitive to the TRPV1-specific vanilloid agonist resiniferatoxin (RTx). Here, we show that mutation of six residues in TRPV3 corresponding to the vanilloid site in TRPV1 is sufficient to engineer RTx binding. However, robust activation of TRPV3 by RTx requires facilitation of channel opening by introducing mutations in the pore, temperatures > 30°C, or sensitization with another agonist. Our results demonstrate that the energetics of channel activation can determine the apparent sensitivity to a stimulus and suggest that allosteric pathways for activation are conserved in the TRPV family.


Subject(s)
Protein Engineering , TRPV Cation Channels/metabolism , Allosteric Regulation/drug effects , Amino Acid Sequence , Animals , Binding Sites , Diterpenes/pharmacology , Mice , Mutation/genetics , Protein Domains , Rats , TRPV Cation Channels/chemistry , Temperature
9.
Science ; 359(6372): 160-161, 2018 01 12.
Article in English | MEDLINE | ID: mdl-29326261
10.
Proc Natl Acad Sci U S A ; 115(2): E317-E324, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29279388

ABSTRACT

The TRPV1 channel is a sensitive detector of pain-producing stimuli, including noxious heat, acid, inflammatory mediators, and vanilloid compounds. Although binding sites for some activators have been identified, the location of the temperature sensor remains elusive. Using available structures of TRPV1 and voltage-activated potassium channels, we engineered chimeras wherein transmembrane regions of TRPV1 were transplanted into the Shaker Kv channel. Here we show that transplanting the pore domain of TRPV1 into Shaker gives rise to functional channels that can be activated by a TRPV1-selective tarantula toxin that binds to the outer pore of the channel. This pore-domain chimera is permeable to Na+, K+, and Ca2+ ions, and remarkably, is also robustly activated by noxious heat. Our results demonstrate that the pore of TRPV1 is a transportable domain that contains the structural elements sufficient for activation by noxious heat.


Subject(s)
Shaker Superfamily of Potassium Channels/metabolism , TRPV Cation Channels/metabolism , Amino Acid Sequence , Animals , Binding Sites , Gene Expression Regulation , HEK293 Cells , Humans , Mice , Models, Molecular , Protein Conformation , Protein Domains , Rats , Recombinant Fusion Proteins
11.
Elife ; 52016 05 13.
Article in English | MEDLINE | ID: mdl-27177419

ABSTRACT

The TRPV1 channel is a detector of noxious stimuli, including heat, acidosis, vanilloid compounds and lipids. The gating mechanisms of the related TRPV2 channel are poorly understood because selective high affinity ligands are not available, and the threshold for heat activation is extremely high (>50°C). Cryo-EM structures of TRPV1 and TRPV2 reveal that they adopt similar structures, and identify a putative vanilloid binding pocket near the internal side of TRPV1. Here we use biochemical and electrophysiological approaches to investigate the resiniferatoxin(RTx) binding site in TRPV1 and to explore the functional relationships between TRPV1 and TRPV2. Collectively, our results support the interaction of vanilloids with the proposed RTx binding pocket, and demonstrate an allosteric influence of a tarantula toxin on vanilloid binding. Moreover, we show that sensitivity to RTx can be engineered into TRPV2, demonstrating that the gating and permeation properties of this channel are similar to TRPV1.


Subject(s)
Diterpenes/metabolism , TRPV Cation Channels/metabolism , Allosteric Regulation , Animals , Binding Sites , Biochemical Phenomena , Electrophysiological Phenomena , Patch-Clamp Techniques , Protein Binding , Protein Conformation , TRPV Cation Channels/chemistry
12.
Elife ; 52016 Feb 10.
Article in English | MEDLINE | ID: mdl-26880553

ABSTRACT

Venom toxins are invaluable tools for exploring the structure and mechanisms of ion channels. Here, we solve the structure of double-knot toxin (DkTx), a tarantula toxin that activates the heat-activated TRPV1 channel. We also provide improved structures of TRPV1 with and without the toxin bound, and investigate the interactions of DkTx with the channel and membranes. We find that DkTx binds to the outer edge of the external pore of TRPV1 in a counterclockwise configuration, using a limited protein-protein interface and inserting hydrophobic residues into the bilayer. We also show that DkTx partitions naturally into membranes, with the two lobes exhibiting opposing energetics for membrane partitioning and channel activation. Finally, we find that the toxin disrupts a cluster of hydrophobic residues behind the selectivity filter that are critical for channel activation. Collectively, our findings reveal a novel mode of toxin-channel recognition that has important implications for the mechanism of thermosensation.


Subject(s)
Cell Membrane/metabolism , Spider Venoms/chemistry , Spider Venoms/metabolism , TRPV Cation Channels/chemistry , TRPV Cation Channels/metabolism , Protein Binding
13.
Elife ; 52016 Feb 12.
Article in English | MEDLINE | ID: mdl-26882503

ABSTRACT

TRPV1 channels in sensory neurons are integrators of painful stimuli and heat, yet how they integrate diverse stimuli and sense temperature remains elusive. Here, we show that external sodium ions stabilize the TRPV1 channel in a closed state, such that removing the external ion leads to channel activation. In studying the underlying mechanism, we find that the temperature sensors in TRPV1 activate in two steps to favor opening, and that the binding of sodium to an extracellular site exerts allosteric control over temperature-sensor activation and opening of the pore. The binding of a tarantula toxin to the external pore also exerts control over temperature-sensor activation, whereas binding of vanilloids influences temperature-sensitivity by largely affecting the open/closed equilibrium. Our results reveal a fundamental role of the external pore in the allosteric control of TRPV1 channel gating and provide essential constraints for understanding how these channels can be tuned by diverse stimuli.


Subject(s)
Ions/metabolism , Sodium/metabolism , TRPV Cation Channels/metabolism , Allosteric Regulation , Benzaldehydes/metabolism , Binding Sites , Protein Binding , Spider Venoms/metabolism
14.
Biophys J ; 104(10): 2160-9, 2013 May 21.
Article in English | MEDLINE | ID: mdl-23708356

ABSTRACT

Thermo-transient receptor potential channels display outstanding temperature sensitivity and can be directly gated by low or high temperature, giving rise to cold- and heat-activated currents. These constitute the molecular basis for the detection of changes in ambient temperature by sensory neurons in animals. The mechanism that underlies the temperature sensitivity in thermo-transient receptor potential channels remains unknown, but has been associated with large changes in standard-state enthalpy (ΔH(o)) and entropy (ΔS(o)) upon channel gating. The magnitude, sign, and temperature dependence of ΔH(o) and ΔS(o), the last given by an associated change in heat capacity (ΔCp), can determine a channel's temperature sensitivity and whether it is activated by cooling, heating, or both, if ΔCp makes an important contribution. We show that in the presence of allosteric gating, other parameters, besides ΔH(o) and ΔS(o), including the gating equilibrium constant, the strength- and temperature dependence of the coupling between gating and the temperature-sensitive transitions, as well as the ΔH(o)/ΔS(o) ratio associated with them, can also determine a channel's temperature-dependent activity, and even give rise to channels that respond to both cooling and heating in a ΔCp-independent manner.


Subject(s)
Ion Channel Gating , Transient Receptor Potential Channels/chemistry , Allosteric Regulation , Animals , Computer Simulation , Entropy , HEK293 Cells , Humans , Kinetics , Temperature
15.
Nat Chem Biol ; 8(1): 78-85, 2011 Nov 20.
Article in English | MEDLINE | ID: mdl-22101604

ABSTRACT

Since 1992, there has been growing evidence that the bioactive phospholipid lysophosphatidic acid (LPA), whose amounts are increased upon tissue injury, activates primary nociceptors resulting in neuropathic pain. The TRPV1 ion channel is expressed in primary afferent nociceptors and is activated by physical and chemical stimuli. Here we show that in control mice LPA produces acute pain-like behaviors, which are substantially reduced in Trpv1-null animals. Our data also demonstrate that LPA activates TRPV1 through a unique mechanism that is independent of G protein-coupled receptors, contrary to what has been widely shown for other ion channels, by directly interacting with the C terminus of the channel. We conclude that TRPV1 is a direct molecular target of the pain-producing molecule LPA and that this constitutes, to our knowledge, the first example of LPA binding directly to an ion channel to acutely regulate its function.


Subject(s)
Lysophospholipids/metabolism , TRPV Cation Channels/metabolism , Animals , Binding Sites , Mice , Mice, Inbred C57BL , Pain/metabolism , Receptors, Lysophosphatidic Acid/metabolism , TRPV Cation Channels/deficiency
16.
Curr Top Med Chem ; 11(17): 2131-50, 2011.
Article in English | MEDLINE | ID: mdl-21671880

ABSTRACT

Transient Receptor Potential (TRP) cation channels participate in several processes of vital importance in cell and organism physiology, and have been demonstrated to participate in the detection of sensory stimuli. The thermo TRP's reviewed: TRPV1 (vanilloid 1), TRPM8 (melastatin 8) and TRPA1 (ankyrin-like 1) are known to integrate different chemical and physical stimuli such as changes in temperature and sensing different irritant or pungent compounds. However, despite the physiological importance of these channels the mechanisms by which they detect incoming stimuli, how the sensing domains are coupled to channel gating and how these processes are connected to specific structural regions in the channel are not fully understood, but valuable information is available. Many sites involved in agonist detection have been characterized and gating models that describe many features of the channel's behavior have been put forward. In this review we will survey some of the key findings concerning the structural and molecular mechanisms of TRPV1, TRPA1 and TRPM8 activation.


Subject(s)
Ion Channel Gating/physiology , Transient Receptor Potential Channels/metabolism , Animals , Humans , Transient Receptor Potential Channels/agonists
17.
J Biol Chem ; 286(28): 24966-76, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21555515

ABSTRACT

The TRPV1 ion channel serves as an integrator of noxious stimuli with its activation linked to pain and neurogenic inflammation. Cholesterol, a major component of cell membranes, modifies the function of several types of ion channels. Here, using measurements of capsaicin-activated currents in excised patches from TRPV1-expressing HEK cells, we show that enrichment with cholesterol, but not its diastereoisomer epicholesterol, markedly decreased wild-type rat TRPV1 currents. Substitutions in the S5 helix, rTRPV1-R579D, and rTRPV1-F582Q, decreased this cholesterol response and rTRPV1-L585I was insensitive to cholesterol addition. Two human TRPV1 variants, with different amino acids at position 585, had different responses to cholesterol with hTRPV1-Ile(585) being insensitive to this molecule. However, hTRPV1-I585L was inhibited by cholesterol addition similar to rTRPV1 with the same S5 sequence. In the absence of capsaicin, cholesterol enrichment also inhibited TRPV1 currents induced by elevated temperature and voltage. These data suggest that there is a cholesterol-binding site in TRPV1 and that the functions of TRPV1 depend on the genetic variant and membrane cholesterol content.


Subject(s)
Cell Membrane/metabolism , Cholesterol/metabolism , Membrane Potentials/physiology , TRPV Cation Channels/metabolism , Amino Acid Motifs , Amino Acid Substitution , Animals , Binding Sites , Capsaicin/pharmacology , Cell Membrane/genetics , Cholesterol/genetics , HEK293 Cells , Humans , Membrane Potentials/drug effects , Mutation, Missense , Rats , Sensory System Agents/pharmacology , Species Specificity , TRPV Cation Channels/genetics
18.
J Biol Chem ; 286(18): 16414-25, 2011 May 06.
Article in English | MEDLINE | ID: mdl-21454671

ABSTRACT

The Kv2.1 channel generates a delayed-rectifier current in neurons and is responsible for modulation of neuronal spike frequency and membrane repolarization in pancreatic ß-cells and cardiomyocytes. As with other tetrameric voltage-activated K(+)-channels, it has been proposed that each of the four Kv2.1 voltage-sensing domains activates independently upon depolarization, leading to a final concerted transition that causes channel opening. The mechanism by which voltage-sensor activation is coupled to the gating of the pore is still not understood. Here we show that the carbon-monoxide releasing molecule 2 (CORM-2) is an allosteric inhibitor of the Kv2.1 channel and that its inhibitory properties derive from the CORM-2 ability to largely reduce the voltage dependence of the opening transition, uncoupling voltage-sensor activation from the concerted opening transition. We additionally demonstrate that CORM-2 modulates Shaker K(+)-channels in a similar manner. Our data suggest that the mechanism of inhibition by CORM-2 may be common to voltage-activated channels and that this compound should be a useful tool for understanding the mechanisms of electromechanical coupling.


Subject(s)
Ion Channel Gating/drug effects , Organometallic Compounds/pharmacology , Potassium Channel Blockers/pharmacology , Shab Potassium Channels/antagonists & inhibitors , Shab Potassium Channels/metabolism , Shaker Superfamily of Potassium Channels/antagonists & inhibitors , Shaker Superfamily of Potassium Channels/metabolism , Allosteric Regulation/drug effects , Allosteric Regulation/physiology , Animals , Insulin-Secreting Cells/metabolism , Ion Channel Gating/physiology , Membrane Potentials/drug effects , Protein Structure, Tertiary , Rats , Shab Potassium Channels/genetics , Shaker Superfamily of Potassium Channels/genetics , Xenopus laevis
19.
Channels (Austin) ; 3(5): 311-3, 2009.
Article in English | MEDLINE | ID: mdl-19713750

ABSTRACT

The era of molecular structure of ion channels has revealed that their transmembrane segments are alpha helices, as was suspected from hydropathy analysis and experimental data. TRP channels are recent additions to the known families of ion channels, and little structural data is available. In a recent work, we explored the conformational changes occurring at the putative S6 segment of TRPV1 channels; and we observed a periodicity of chemical modification of residues suggestive of an alpha helical structure. Further analysis of the periodicity of the disposition of hydrophobic residues in the S6 segment, suggests that the general architecture of the TRPV1 S6 segment, is very similar to that of voltage-dependent channels of known structure--an aqueous cavity lined by an amphipathic alpha helix, with most of the hydrophobic residues pointing into it.


Subject(s)
TRPV Cation Channels/chemistry , Animals , Biophysics/methods , Cryoelectron Microscopy/methods , Humans , Hydrophobic and Hydrophilic Interactions , Ion Channels/chemistry , Ions , Protein Conformation , Protein Structure, Secondary
20.
Nat Struct Mol Biol ; 16(7): 704-10, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19561608

ABSTRACT

Transient receptor potential vanilloid 1 (TRPV1) channels mediate several types of physiological responses. Despite the importance of these channels in pain detection and inflammation, little is known about how their structural components convert different types of stimuli into channel activity. To localize the activation gate of these channels, we inserted cysteines along the S6 segment of mutant TRPV1 channels and assessed their accessibility to thiol-modifying agents. We show that access to the pore of TRPV1 is gated by S6 in response to both capsaicin binding and increases in temperature, that the pore-forming S6 segments are helical structures and that two constrictions are present in the pore: one that impedes the access of large molecules and the other that hampers the access of smaller ions and constitutes an activation gate of these channels.


Subject(s)
Models, Molecular , Protein Structure, Secondary , Protein Structure, Tertiary , TRPV Cation Channels/chemistry , TRPV Cation Channels/metabolism , Amino Acid Sequence , Animals , Capsaicin/metabolism , Cysteine/chemistry , Ion Channel Gating/physiology , Ions/metabolism , Leucine/chemistry , Mesylates/chemistry , Molecular Sequence Data , Rats , Sensory System Agents/metabolism , TRPV Cation Channels/genetics , Temperature , Tyrosine/chemistry
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