scholarly journals Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Cinder Faith Cohen ◽  
Arthur Silveira Prudente ◽  
Temugin Berta ◽  
Sang Hoon Lee
Keyword(s):  
Chronic Migraine ◽  
Small Molecule ◽  
Transient Receptor Potential ◽  
Treatment Options ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Male And Female ◽  
Female Mice ◽  
Transient Receptor

Migraine is a common neurological disorder with few available treatment options. Recently, we have demonstrated the role of transient receptor potential cation channel subfamily C member 4 (TRPC4) in itch and the modulation of the calcitonin gene-related peptide (CGRP), a biomarker and emerging therapeutic target for migraine. In this study, we characterized the role of TRPC4 in pain and evaluated its inhibition as anti-migraine pain therapy in preclinical mouse models. First, we found that TRPC4 is highly expressed in trigeminal ganglia and its activation not only mediates itch but also pain. Second, we demonstrated that the small-molecule inhibitor ML204, a specific TRPC4 antagonist, significantly reduced episodic and chronic migraine-like behaviors in male and female mice after injection of nitroglycerin (NTG), a well-known migraine inducer in rodents and humans. Third, we found a significant decrease in CGRP protein levels in the plasma of both male and female mice treated with ML-204, which largely prevented the development of chronic migraine-like behavior. Using sensory neuron cultures, we confirmed that activation of TRPC4 elicited release of CGRP, which was significantly diminished by ML-204. Collectively, our findings identify TRPC4 in peripheral sensory neurons as a mediator of CGRP release and NTG-evoked migraine. Since a TRPC4 antagonist is already in clinical trials, we expect that this study will rapidly lead to novel and effective clinical treatments for migraineurs.

Role of capacitative Ca2+ entry in bronchial contraction and remodeling

2002 ◽  
Vol 92 (4) ◽  
pp. 1594-1602 ◽  
Author(s):  
Michele Sweeney ◽  
Sharon S. McDaniel ◽  
Oleksandr Platoshyn ◽  
Shen Zhang ◽  
Ying Yu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Bronchial Hyperresponsiveness ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Wall Thickening ◽  
Bronchial Wall ◽  
Intracellular Ca ◽  
Transient Receptor

Asthma is characterized by airway inflammation, bronchial hyperresponsiveness, and airway obstruction by bronchospasm and bronchial wall thickening due to smooth muscle hypertrophy. A rise in cytosolic free Ca2+ concentration ([Ca2+]cyt) may serve as a shared signal transduction element that causes bronchial constriction and bronchial wall thickening in asthma. In this study, we examined whether capacitative Ca2+ entry (CCE) induced by depletion of intracellular Ca2+ stores was involved in agonist-mediated bronchial constriction and bronchial smooth muscle cell (BSMC) proliferation. In isolated bronchial rings, acetylcholine (ACh) induced a transient contraction in the absence of extracellular Ca2+ because of Ca2+ release from intracellular Ca2+ stores. Restoration of extracellular Ca2+in the presence of atropine, an M-receptor blocker, induced a further contraction that was apparently caused by a rise in [Ca2+]cyt due to CCE. In single BSMC, amplitudes of the store depletion-activated currents ( I SOC) and CCE were both enhanced when the cells proliferate, whereas chelation of extracellular Ca2+ with EGTA significantly inhibited the cell growth in the presence of serum. Furthermore, the mRNA expression of TRPC1, a transient receptor potential channel gene, was much greater in proliferating BSMC than in growth-arrested cells. Blockade of the store-operated Ca2+channels by Ni2+ decreased I SOC and CCE and markedly attenuated BSMC proliferation. These results suggest that upregulated TRPC1 expression, increased I SOC, enhanced CCE, and elevated [Ca2+]cyt may play important roles in mediating bronchial constriction and BSMC proliferation.

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.

scholarly journals The Role of Transient Receptor Potential Channel 6 Channels in the Pulmonary Vasculature

2017 ◽  
Vol 8 ◽  
Author(s):  
Monika Malczyk ◽  
Alexandra Erb ◽  
Christine Veith ◽  
Hossein Ardeschir Ghofrani ◽  
Ralph T. Schermuly ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Pulmonary Vasculature ◽  
Transient Receptor

scholarly journals Trpc5 deficiency causes hypoprolactinemia and altered function of oscillatory dopamine neurons in the arcuate nucleus

2019 ◽  
Vol 116 (30) ◽  
pp. 15236-15243 ◽  
Author(s):  
Thomas Blum ◽  
Ana Moreno-Pérez ◽  
Martina Pyrski ◽  
Bernd Bufe ◽  
Anela Arifovic ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Normal Function ◽  
The Body ◽  
Dopamine Neurons ◽  
Potential Oscillations ◽  
Female Mice ◽  
Transient Receptor

Dopamine neurons of the hypothalamic arcuate nucleus (ARC) tonically inhibit the release of the protein hormone prolactin from lactotropic cells in the anterior pituitary gland and thus play a central role in prolactin homeostasis of the body. Prolactin, in turn, orchestrates numerous important biological functions such as maternal behavior, reproduction, and sexual arousal. Here, we identify the canonical transient receptor potential channel Trpc5 as an essential requirement for normal function of dopamine ARC neurons and prolactin homeostasis. By analyzing female mice carrying targeted mutations in the Trpc5 gene including a conditional Trpc5 deletion, we show that Trpc5 is required for maintaining highly stereotyped infraslow membrane potential oscillations of dopamine ARC neurons. Trpc5 is also required for eliciting prolactin-evoked tonic plateau potentials in these neurons that are part of a regulatory feedback circuit. Trpc5 mutant females show severe prolactin deficiency or hypoprolactinemia that is associated with irregular reproductive cyclicity, gonadotropin imbalance, and impaired reproductive capabilities. These results reveal a previously unknown role for the cation channel Trpc5 in prolactin homeostasis of female mice and provide strategies to explore the genetic basis of reproductive disorders and other malfunctions associated with defective prolactin regulation in humans.

scholarly journals Deletion of cardiac polycystin 2/PC2 results in increased SR calcium release and blunted adrenergic reserve

2020 ◽  
Vol 319 (5) ◽  
pp. H1021-H1035
Author(s):  
Elisabeth DiNello ◽  
Elisa Bovo ◽  
Paula Thuo ◽  
Thomas G. Martin ◽  
Jonathan A. Kirk ◽  
...  
Keyword(s):  
Calcium Release ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Adult Onset ◽  
Cardiac Dyssynchrony ◽  
Intracellular Calcium Signaling ◽  
Transient Receptor ◽  
Sr Calcium Release

Our goal was to characterize the role of the transient receptor potential channel polycystin 2 (PC2) in cardiomyocytes following adult-onset deletion. Loss of PC2 resulted in decreased cardiac shortening and cardiac dyssynchrony and diminished adrenergic reserve. These results suggest that cardiac-specific PC2 modulates intracellular calcium signaling and contributes to the maintenance of adrenergic pathways.

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