Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein

Banzawa, Nagako; Saito, Shigeru; Imagawa, Toshiaki; Kashio, Makiko; Takahashi, Kenji; Tominaga, Makoto; Ohta, Toshio

doi:10.1074/jbc.m114.586891

Cited by 34 publications

(19 citation statements)

References 45 publications

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“…Many research groups, including our own, have previously attempted to identify the binding mechanisms or the effective sites for potent mammalian TRPA1 antagonists. While the action sites of A96 and AP-18, which are structurally similar, were discovered912131425, those of HC remained undetermined. It is well documented that the effects of TRPA1 antagonists differ in a species-specific manner; therefore, we utilized these species-specific differences to identify the sites of the antagonistic activity of HC.…”

Section: Discussionmentioning

confidence: 99%

“…Due to this species diversity, comparative analysis of TRPA1 among different species has proven informative for understanding structure-function relationships89. For example, A967079 (A96) and AP18, both of which are structurally similar, are potent mammalian TRPA1 antagonists, although their inhibitory effects on TRPA1 vary among species101112. Comparative and mutagenesis experiments with TRPA1 from different species revealed that several amino acids in the TM5 domain are crucial to the effects of these two antagonists91213.…”

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confidence: 99%

“…For example, A967079 (A96) and AP18, both of which are structurally similar, are potent mammalian TRPA1 antagonists, although their inhibitory effects on TRPA1 vary among species101112. Comparative and mutagenesis experiments with TRPA1 from different species revealed that several amino acids in the TM5 domain are crucial to the effects of these two antagonists91213. Furthermore, a recent study reporting the detailed structure of human TRPA1 identified a binding site for A96 that is in the vicinity of sites found previously14.…”

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confidence: 99%

“…The inhibitory effect of HC also differs among species. While HC inhibits TRPA1 from green anole and chicken, it fails to inhibit western clawed frog TRPA1 (fTRPA1) in a heterologous expression system1012. Therefore, we attempted to identify amino acid residues (or regions) involved in the inhibitory effects of HC in order to understand the molecular mechanism of TRPA1 inhibition.…”

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confidence: 99%

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Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Gupta

Saito

Mori

et al. 2016

Sci Rep

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Pain is a harmful sensation that arises from noxious stimuli. Transient receptor potential ankyrin 1 (TRPA1) is one target for studying pain mechanisms. TRPA1 is activated by various stimuli such as noxious cold, pungent natural products and environmental irritants. Since TRPA1 is an attractive target for pain therapy, a few TRPA1 antagonists have been developed and some function as analgesic agents. The responses of TRPA1 to agonists and antagonists vary among species and these species differences have been utilized to identify the structural basis of activation and inhibition mechanisms. The TRPA1 antagonist HC-030031 (HC) failed to inhibit frog TRPA1 (fTRPA1) and zebrafish TRPA1 activity induced by cinnamaldehyde (CA), but did inhibit human TRPA1 (hTRPA1) in a heterologous expression system. Chimeric studies between fTRPA1 and hTRPA1, as well as analyses using point mutants, revealed that a single amino acid residue (N855 in hTRPA1) significantly contributes to the inhibitory action of HC. Moreover, the N855 residue and the C-terminus region exhibited synergistic effects on the inhibition by HC. Molecular dynamics simulation suggested that HC stably binds to hTRPA1-N855. These findings provide novel insights into the structure-function relationship of TRPA1 and could lead to the development of more effective analgesics targeted to TRPA1.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Gupta

Saito

Mori

et al. 2016

Sci Rep

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“…7,8 (B) Structures of a tetrameric (inset) or a single subunit of human TRPA1 are shown with critical amino acids involved in activation or inhibition by A-967079, HC-030031, and methyl anthranilate highlighted in cyan, magenta, and green, respectively. 11,52,63,69,70,72 Critical amino acids involved in TRPA1 sensitivity to MA were identified using chicken TRPA1. 52 TM, transmembrane domain; PH, pore helix; ARD, ankyrin repeat domain.…”

Section: Thermosensitive Transient Receptor Potential Channels As Thementioning

confidence: 99%

Evolutionary tuning of TRPA1 and TRPV1 thermal and chemical sensitivity in vertebrates

Saito

Tominaga

2017

Temperature

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Thermal perception is an essential sensory system for survival since temperature fluctuations affect various biologic processes. Therefore, evolutionary changes in thermosensory systems may have played important roles in adaptation processes. Comparative analyses of sensory receptors among different species can provide us with important clues to understand the molecular basis for adaptation. Several ion channels belonging to the transient receptor potential (TRP) superfamily serve as thermal sensors in a wide variety of animal species. These TRP proteins are multimodal receptors that are activated by temperature as well as other sensory stimuli. Among them TRPV1 and TRPA1 are activated by noxious ranges of thermal stimuli and irritating chemicals, and are mainly expressed in nociceptive sensory neurons. Comparative analyses of TRPV1 and TRPA1 among various vertebrate species revealed evolutionary changes that likely contributed to diversification of sensory perception. Whereas heat-induced TRPV1 responses have been conserved across many vertebrates, TRPA1 varied among species. Mutagenesis experiments using these two channels from various species also helped characterize the molecular basis for their activation and inhibition. Meanwhile, recent detailed comparative analyses using closely related species showed shifts in TRPV1 and TRPA1 thermal sensitivity that allowed adaptation to different thermal environments. Changes in TRPV1 heat responses appear to arise from just a few amino acid differences among species. These observations suggest that evolutionary changes in peripheral sensors are likely driving force for shifting thermal perception in adaptation processes.

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Neuronal differentiation in the developing human spinal ganglia

Vukojević

Filipović

Sedlar

et al. 2016

The Anatomical Record

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The spatiotemporal developmental pattern of the neural crest cells differentiation toward the first appearance of the neuronal subtypes was investigated in developing human spinal ganglia (SG) between the fifth and tenth developmental week using immunohistochemistry and immunofluorescence methods. First neurofilament-200-(NF200, likely myelinated mechanoreceptors) and isolectin-B4-positive neurons (likely unmyelinated nociceptors) appeared already in the 5/6th developmental week and their number subsequently increased during the progression of development. Proportion of NF200-positive cells was higher in the ventral parts of the SG than in the dorsal parts, particularly during the 5/6th and 9/10th developmental weeks (Mann-Whitney, P 5 0.040 and P 5 0.003). NF200 and IB4 colocalized during the whole investigated period. calcitonin gene-related peptide (CGRP; nociceptive responses), vanilloid receptor-1 (VR1; polymodal nociceptors), and calretinin (calcium signaling) cell immunoreactivity first appeared in the sixth week and eighth week, respectively, especially in the dorsal parts of the SG. VR1 and CGRP colocalized with NF00 during the whole investigated period. Our results indicate the high potential of early differentiated neuronal cells, which slightly decreased with the progression of SG differentiation. On the contrary, the number of neuronal subtypes displayed increasing differentiation at later developmental stage. The great diversity of phenotypic expression found in the SG neurons is the result of a wide variety of influences, occurring at different stages of development in a large potential repertory of these neurons. Understanding the pathway of neural differentiation in the human, SG could be important for the studies dealing with the process of regeneration of damaged spinal nerves or during the repair of pathological changes within the affected ganglia.

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Molecular Basis Determining Inhibition/Activation of Nociceptive Receptor TRPA1 Protein

Cited by 34 publications

References 45 publications

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Structural basis of TRPA1 inhibition by HC-030031 utilizing species-specific differences

Evolutionary tuning of TRPA1 and TRPV1 thermal and chemical sensitivity in vertebrates

Neuronal differentiation in the developing human spinal ganglia

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