Role of the Outer Pore Domain in Transient Receptor Potential Vanilloid 1 Dynamic Permeability to Large Cations

Munns, Clare H.; Chung, Man‐Kyo; Sánchez, Yuly E.; Amzel, L. Mario; Caterina, Michael J.

doi:10.1074/jbc.m114.597435

Cited by 48 publications

(44 citation statements)

References 49 publications

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“…As a result, to adequately control the concentrations of ions when recording under bi-ionic conditions, the membrane conductance ( σ mem ) must be sufficiently small ( σ mem × R access ≪ 1; see Methods). The present results with P2X receptors, together with our reservoir model, provide sufficient motivation to reexamine the phenomenon of dynamic ion selectivity reported for TRPV1 channels 17, 18 , TRPA1 channels 47, 48 , ASICs 19, 20 , and TMEM16A calcium-activated Cl - channels 49, 50 . Dynamic ion selectivity for TRPV1 channels requires high agonist concentrations and high channel density 17 , and these channels have an appreciable permeability to NMDG + 17 and dyes 17, 40 , raising the possibility that ion depletion and accumulation may be responsible for the reported changes in ion selectivity of these channels.…”

Section: Discussionsupporting

confidence: 66%

“…Voltage-activated potassium (Kv), sodium (Nav) and calcium (Cav) channels, for example, contain ion selectivity filters (containing ion binding sites) at the extracellular end of their pores 2, 3 that impart exquisite ion selectivity and enable them to play key roles in the generation and propagation of action potentials, or in excitation-secretion and excitation-contraction coupling 1 . However, a large number of studies on P2X receptor channels 4-16 , TRPV1 channels 17, 18 and ASICs 19, 20 have reported that ion selectivity can change dynamically in response to agonist activation. In the case of P2X receptors, the prevailing view is that the pore initially opens rapidly to a conducting state that is relatively selective for small cations (such as Na + , K + and Ca 2+ ), but then gradually dilates over time to become more permeable to large organic cations such as N-methyl-D-glucamine (NMDG + ), as well as to fluorophores as large as 14Å 4-16 .…”

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confidence: 99%

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Physical basis of apparent pore dilation of ATP-activated P2X receptor channels

et al. 2015

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The selectivity of ion channels is fundamental for their roles in electrical and chemical signaling, and ion homeostasis. Although most ion channels exhibit stable ion selectivity, the prevailing view for purinergic P2X receptor channels, transient receptor potential V1 (TRPV1) channels and acid sensing ion channels (ASICs) is that their ion conduction pores dilate upon prolonged activation. We investigated this mechanism in P2X receptors and found that the hallmark shift in equilibrium potential observed with prolonged channel activation does not result from pore dilation, but from time-dependent alterations in the concentration of intracellular ions. We derived a physical model to calculate ion concentration changes during patch-clamp recordings, which validates our experimental findings and provides a quantitative guideline for effectively controlling ion concentration. Our results have fundamental implications for understanding ion permeation and gating in P2X receptor channels, and more broadly for using patch-clamp techniques to study ion channels and neuronal excitability.

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Section: Discussionsupporting

confidence: 66%

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confidence: 99%

Physical basis of apparent pore dilation of ATP-activated P2X receptor channels

et al. 2015

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“…Specifically, a B30 amino acid loop connecting S5 with the pore helix, known as the pore turret ( Fig. 4a), has been implicated in channel gating, large organic cation permeation and pore dilation 33,34 . Mutation of key residues within the TRPV1 pore turret (Gly 618 and Ser 629), which are conserved in TRPV2 (Gly 582 and Ser 592; Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure of the Full-Length TRPV2 Channel by Cryo-EM

et al. 2016

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Transient receptor potential (TRP) proteins form a superfamily Ca 2 þ -permeable cation channels regulated by a range of chemical and physical stimuli. Structural analysis of a 'minimal' TRP vanilloid subtype 1 (TRPV1) elucidated a mechanism of channel activation by agonists through changes in its outer pore region. Though homologous to TRPV1, other TRPV channels (TRPV2-6) are insensitive to TRPV1 activators including heat and vanilloids. To further understand the structural basis of TRPV channel function, we determined the structure of full-length TRPV2 at B5 Å resolution by cryo-electron microscopy. Like TRPV1, TRPV2 contains two constrictions, one each in the pore-forming upper and lower gates. The agonist-free full-length TRPV2 has wider upper and lower gates compared with closed and agonist-activated TRPV1. We propose these newly revealed TRPV2 structural features contribute to diversity of TRPV channels.

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“…M644 is located in the selectivity filter, which is accomplished in the open state of the upper gate21. The mutation M644I was reported to decrease the permeability of NMDG for rat (r) TRPV123. I679 is located in the S6 segment of rTRPV1 protein and is suggested to be part of the lower gate2122.…”

Section: Resultsmentioning

confidence: 99%

Lactate is a potent inhibitor of the capsaicin receptor TRPV1

Roche

Walther

Leonow

et al. 2016

Sci Rep

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Tissue ischemia results in an accumulation of lactate and local or systemic lactic acidosis. In nociceptive sensory neurons, lactate was reported to sensitize or activate the transient receptor potential ion channel TRPA1 and acid-sensing ion channels (ASICs). However, it is unclear how lactate modulates the TRPV1 regarded as the main sensor for acidosis in sensory neurons. In this study we investigated the effects of lactate (LA) on recombinant and native TRPV1 channels and on TRPV1-mediated release of neuropeptides from mouse nerves. TRPV1-mediated membrane currents evoked by protons, capsaicin or heat are inhibited by LA at concentrations ranging from 3 μM to 100 mM. LA inhibits TRPV1-mediated proton-induced Ca2+-influx in dorsal root ganglion neurons as well as proton-evoked neuropeptide release from mouse nerves. Inhibition of TRPV1 by LA is significantly stronger on inward currents as compared to outward currents since LA affects channel gating, shifting the activation curve towards more positive potentials. The mutation I680A in the pore lower gate displays no LA inhibition. Cell-attached as well as excised inside- and outside-out patches suggest an interaction through an extracellular binding site. In conclusion, our data demonstrate that lactate at physiologically relevant concentrations is a potent endogenous inhibitor of TRPV1.

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Role of the Outer Pore Domain in Transient Receptor Potential Vanilloid 1 Dynamic Permeability to Large Cations

Cited by 48 publications

References 49 publications

Physical basis of apparent pore dilation of ATP-activated P2X receptor channels

Physical basis of apparent pore dilation of ATP-activated P2X receptor channels

Structure of the Full-Length TRPV2 Channel by Cryo-EM

Lactate is a potent inhibitor of the capsaicin receptor TRPV1

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