scholarly journals A small molecule screen identifies novel inhibitors of mechanosensory nematocyst discharge in Hydra

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Diana Hofmann ◽  
Niharika Garg ◽  
Simone Grässle ◽  
Sylvia Vanderheiden ◽  
Bruno Gideon Bergheim ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hair Cells ◽  
Transient Receptor Potential ◽  
Prey Capture ◽  
Receptor Potential ◽  
Mechanical Stimulus ◽  
Core Motif ◽  
Structure Activity ◽  
Small Molecule Screen ◽  
Transient Receptor

AbstractCnidarians are characterized by the possession of stinging organelles, called nematocysts, which they use for prey capture and defense. Nematocyst discharge is controlled by a mechanosensory apparatus with analogies to vertebrate hair cells. Members of the transient receptor potential (TRPN) ion channel family are supposed to be involved in the transduction of the mechanical stimulus. A small molecule screen was performed to identify compounds that affect nematocyst discharge in Hydra. We identified several [2.2]paracyclophanes that cause inhibition of nematocyst discharge in the low micro-molar range. Further structure–activity analyses within the compound class of [2.2]paracyclophanes showed common features that are required for the inhibitory activity of the [2.2]paracyclophane core motif. This study demonstrates that Hydra can serve as a model for small molecule screens targeting the mechanosensory apparatus in native tissues.

scholarly journals Peripheral Mechanobiology of Touch—Studies on Vertebrate Cutaneous Sensory Corpuscles

2020 ◽  
Vol 21 (17) ◽  
pp. 6221 ◽  
Author(s):  
Ramón Cobo ◽  
Jorge García-Piqueras ◽  
Yolanda García-Mesa ◽  
Jorge Feito ◽  
Olivia García-Suárez ◽  
...  
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Mechanical Stimulus ◽  
Nerve Fibers ◽  
Current Data ◽  
Acid Sensing Ion Channels ◽  
Low Threshold ◽  
Transient Receptor

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aβ nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

Modulation of the Transient Receptor Potential Vanilloid Channel TRPV4 by 4α-Phorbol Esters: A Structure−Activity Study

2009 ◽  
Vol 52 (9) ◽  
pp. 2933-2939 ◽  
Author(s):  
Thomas Kjær Klausen ◽  
Alberto Pagani ◽  
Alberto Minassi ◽  
Abdellah Ech-Chahad ◽  
Jean Prenen ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Phorbol Esters ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Structure Activity ◽  
Transient Receptor

scholarly journals Preface by the Editor

2013 ◽  
Vol 6 (1) ◽  
pp. 7-7
Author(s):  
Arpad Szallasi
Keyword(s):  
Clinical Trials ◽  
Pain Relief ◽  
Small Molecule ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Analgesic Drugs ◽  
The Past ◽  
Pharmacological Targets ◽  
Transient Receptor

With over 600 reviews, Transient Receptor Potential (TRP) channels arguably represent today’s most extensively reviewed pharmacological targets. The literature on TRP channels is vast and still growing: it has exploded from a mere 21 papers in 1995 to over 2,000 in the past two years. In the past fifteen years, the field had shown spectacular progress. From the cloning of the vanilloid (capsaicin) recep a novel class of analgesic agents.tor TRPV1 in 1997 it has taken only a decade for the first small molecule TRPV1 antagonists to enter clinical trials as So why to add another review collection to this already overwhelming body of literature? First, new therapeutic tar-gets are emerging (e.g. TRPA1 and TRPV3) that look even more promising than TRPV1. Second, even the most studied TRP channel, TRPV1, continues to surprise. One might ar-gue that we are still at the beginning of the long and arduous road to obtain clinically useful analgesic drugs targeting TRP channels. It remains to be discovered if TRP channels are really Targets for Pain Relief, but it has already been clear that Bernd Nilius was right in calling TRP channels “Truly Remarkable Proteins.”

scholarly journals TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype

2018 ◽  
Vol 115 (48) ◽  
pp. 12301-12306 ◽  
Author(s):  
Wei Chou Tseng ◽  
David C. Pryde ◽  
Katrina E. Yoger ◽  
Karen M. Padilla ◽  
Brett M. Antonio ◽  
...  
Keyword(s):  
Small Molecule ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Structural Class ◽  
Drug Candidates ◽  
Novel Structure ◽  
Transient Receptor ◽  
Preclinical Animal Models ◽  
The Individual

TRPA1, a member of the transient receptor potential channel (TRP) family, is genetically linked to pain in humans, and small molecule inhibitors are efficacious in preclinical animal models of inflammatory pain. These findings have driven significant interest in development of selective TRPA1 inhibitors as potential analgesics. The majority of TRPA1 inhibitors characterized to date have been reported to interact with the S5 transmembrane helices forming part of the pore region of the channel. However, the development of many of these inhibitors as clinical drug candidates has been prevented by high lipophilicity, low solubility, and poor pharmacokinetic profiles. Identification of alternate compound interacting sites on TRPA1 provides the opportunity to develop structurally distinct modulators with novel structure-activity relationships and more desirable physiochemical properties. In this paper, we have identified a previously undescribed potent and selective small molecule thiadiazole structural class of TRPA1 inhibitor. Using species ortholog chimeric and mutagenesis strategies, we narrowed down the site of interaction to ankyrinR #6 within the distal N-terminal region of TRPA1. To identify the individual amino acid residues involved, we generated a computational model of the ankyrinR domain. This model was used predictively to identify three critical amino acids in human TRPA1, G238, N249, and K270, which were confirmed by mutagenesis to account for compound activity. These findings establish a small molecule interaction region on TRPA1, expanding potential avenues for developing TRPA1 inhibitor analgesics and for probing the mechanism of channel gating.

Sign in / Sign up

Export Citation Format

Share Document