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12 pages, 3190 KiB

Open AccessArticle

Functional TRPA1 Channels Regulate CD56^dimCD16⁺ NK Cell Cytotoxicity against Tumor Cells

by Fernanda Scopelliti, Valentina Dimartino, Caterina Cattani and Andrea Cavani

Int. J. Mol. Sci. 2023, 24(19), 14736; https://doi.org/10.3390/ijms241914736 - 29 Sep 2023

Cited by 3 | Viewed by 1379

Abstract

Transient receptor potential ankyrin 1 (TRPA1) channels are expressed on the surface of different cell types, including immune cells. However, TRPA1’s role in the context of innate and adaptive immune responses has not been fully elucidated so far. In this study, we aimed [...] Read more.

Transient receptor potential ankyrin 1 (TRPA1) channels are expressed on the surface of different cell types, including immune cells. However, TRPA1’s role in the context of innate and adaptive immune responses has not been fully elucidated so far. In this study, we aimed at investigating the expression and function of TRPA1 channels on NK cells. Among NK cells, TRPA1 was highly expressed by the CD56^dimCD16⁺ subpopulation, but not by CD56^brightCD16⁻ cells, as detected by FACS. TRPA1 activation with the potent ligand allyl isothiocyanate (AITC) induces intracellular calcium flux in CD56^dimCD16⁺ cells, which was prevented by the TRPA1 antagonist HC-030031. AITC treatment increased the membrane around NKp44 and strongly decreased CD16 and CD8 expression, while CD158a, CD159a, NKG2d, NKp46 were substantially unaffected. Importantly, AITC increased the granzyme production and CD107 expression and increased NK cell-mediated cytotoxicity towards the K562 cell line and two different melanoma cell lines. In parallel, TRPA1 activation also plays regulatory roles by affecting the survival of NK cells to limit uncontrolled and prolonged NK cell-mediated cytotoxicity. Our results indicate that the activation of TRPA1 is an important regulatory signal for NK cells, and agonists of TRPA1 could be used to strengthen the tumor response of the immune system. Full article

(This article belongs to the Special Issue TRP Channel)

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13 pages, 2092 KiB

Open AccessArticle

Role of TRPC3 in Right Ventricular Dilatation under Chronic Intermittent Hypoxia in 129/SvEv Mice

by Do-Yang Park, Woon Heo, Miran Kang, Taeyoung Ahn, DoHyeon Kim, Ayeon Choi, Lutz Birnbaumer, Hyung-Ju Cho and Joo Young Kim

Int. J. Mol. Sci. 2023, 24(14), 11284; https://doi.org/10.3390/ijms241411284 - 10 Jul 2023

Viewed by 1710

Abstract

Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule responsible for the pathogenesis remains unknown. Given the resistance to RV dilation observed in transient receptor potential canonical 3(Trpc3)^−/− [...] Read more.

Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule responsible for the pathogenesis remains unknown. Given the resistance to RV dilation observed in transient receptor potential canonical 3(Trpc3)^−/− mice during a pulmonary hypertension model induced by phenylephrine (PE), we hypothesized that TRPC3 also plays a role in chronic intermittent hypoxia (CIH) conditions, which lead to RV dilation and dysfunction. To test this, we established an OSA mouse model using 8- to 12-week-old 129/SvEv wild-type and Trpc3^−/− mice in a customized breeding chamber that simulated sleep and oxygen cycles. Functional parameters of the RV were evaluated through analysis of cardiac cine magnetic resonance images, while histopathological examinations were conducted on cardiomyocytes and pulmonary vessels. Following exposure to 4 weeks of CIH, Trpc3^−/− mice exhibited significant RV dysfunction, characterized by decreased ejection fraction, increased end-diastole RV wall thickness, and elevated expression of pathological cardiac markers. In addition, reactive oxygen species (ROS) signaling and the endothelin system were markedly increased solely in the hearts of CIH-exposed Trpc3^−/− mice. Notably, no significant differences in pulmonary vessel thickness or the endothelin system were observed in the lungs of wild-type (WT) and Trpc3^−/− mice subjected to 4 weeks of CIH. In conclusion, our findings suggest that TRPC3 serves as a regulator of RV resistance in response to pressure from the pulmonary vasculature, as evidenced by the high susceptibility to RV dilation in Trpc3^−/− mice without notable changes in pulmonary vasculature under CIH conditions. Full article

(This article belongs to the Special Issue TRP Channel)

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12 pages, 798 KiB

Open AccessArticle

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain

by Yoshinori Aoki, Daisuke Nishizawa, Seii Ohka, Shinya Kasai, Hideko Arita, Kazuo Hanaoka, Choku Yajima, Masako Iseki, Jitsu Kato, Setsuro Ogawa, Ayako Hiranuma, Junko Hasegawa, Kyoko Nakayama, Yuko Ebata, Tatsuya Ichinohe, Masakazu Hayashida, Ken-ichi Fukuda and Kazutaka Ikeda

Int. J. Mol. Sci. 2023, 24(2), 1028; https://doi.org/10.3390/ijms24021028 - 5 Jan 2023

Cited by 2 | Viewed by 1830

Abstract

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage [...] Read more.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain. Full article

(This article belongs to the Special Issue TRP Channel)

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20 pages, 8287 KiB

Open AccessArticle

Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice

by Vibhu Kumar, Vijay Kumar, Kirti Devi, Ajay Kumar, Rehan Khan, Ravindra Pal Singh, Sivasubramanian Rajarammohan, Kanthi Kiran Kondepudi, Kanwaljit Chopra and Mahendra Bishnoi

Int. J. Mol. Sci. 2022, 23(17), 9577; https://doi.org/10.3390/ijms23179577 - 24 Aug 2022

Cited by 6 | Viewed by 2881

Abstract

Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and [...] Read more.

Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and luminal microbial community. The present study focuses on the effects’ intra rectal administration of capsazepine (modulator of TRPA1/TRPV1 expressing peptidergic sensory neurons) on colonic mucus production and gut health. We performed histological analysis, gut permeability alteration, gene expression changes, metabolite profiling, and gut microbial abundance in the ileum, colon, and cecum content of these animals. Intra rectal administration of capsazepine modulates TRPA1/TRPV1-positive nociceptors (behavioral pain assays) and resulted in damaged mucosal lining, increased gut permeability, and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. These results suggest that caution must be exercised before employing TRPA1/TRPV1 modulation as a therapeutic option to alleviate pain caused due to IBD. Full article

(This article belongs to the Special Issue TRP Channel)

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Review

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18 pages, 1486 KiB

Open AccessReview

A Putative Role for TRPC6 in Immune-Mediated Kidney Injury

by Daan C. ‘t Hart, Johan van der Vlag and Tom Nijenhuis

Int. J. Mol. Sci. 2023, 24(22), 16419; https://doi.org/10.3390/ijms242216419 - 16 Nov 2023

Viewed by 1489

Abstract

Excessive activation of the immune system is the cause of a wide variety of renal diseases. However, the pathogenic mechanisms underlying the aberrant activation of the immune system in the kidneys often remain unknown. TRPC6, a member of the Ca²⁺-permeant family [...] Read more.

Excessive activation of the immune system is the cause of a wide variety of renal diseases. However, the pathogenic mechanisms underlying the aberrant activation of the immune system in the kidneys often remain unknown. TRPC6, a member of the Ca²⁺-permeant family of TRPC channels, is important in glomerular epithelial cells or podocytes for the process of glomerular filtration. In addition, TRPC6 plays a crucial role in the development of kidney injuries by inducing podocyte injury. However, an increasing number of studies suggest that TRPC6 is also responsible for tightly regulating the immune cell functions. It remains elusive whether the role of TRPC6 in the immune system and the pathogenesis of renal inflammation are intertwined. In this review, we present an overview of the current knowledge of how TRPC6 coordinates the immune cell functions and propose the hypothesis that TRPC6 might play a pivotal role in the development of kidney injury via its role in the immune system. Full article

(This article belongs to the Special Issue TRP Channel)

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23 pages, 2587 KiB

Open AccessReview

Resiniferatoxin: Nature’s Precision Medicine to Silence TRPV1-Positive Afferents

by Arpad Szallasi

Int. J. Mol. Sci. 2023, 24(20), 15042; https://doi.org/10.3390/ijms242015042 - 10 Oct 2023

Cited by 13 | Viewed by 3477

Abstract

Resiniferatoxin (RTX) is an ultrapotent capsaicin analog with a unique spectrum of pharmacological actions. The therapeutic window of RTX is broad, allowing for the full desensitization of pain perception and neurogenic inflammation without causing unacceptable side effects. Intravesical RTX was shown to restore [...] Read more.

Resiniferatoxin (RTX) is an ultrapotent capsaicin analog with a unique spectrum of pharmacological actions. The therapeutic window of RTX is broad, allowing for the full desensitization of pain perception and neurogenic inflammation without causing unacceptable side effects. Intravesical RTX was shown to restore continence in a subset of patients with idiopathic and neurogenic detrusor overactivity. RTX can also ablate sensory neurons as a “molecular scalpel” to achieve permanent analgesia. This targeted (intrathecal or epidural) RTX therapy holds great promise in cancer pain management. Intra-articular RTX is undergoing clinical trials to treat moderate-to-severe knee pain in patients with osteoarthritis. Similar targeted approaches may be useful in the management of post-operative pain or pain associated with severe burn injuries. The current state of this field is reviewed, from preclinical studies through veterinary medicine to clinical trials. Full article

(This article belongs to the Special Issue TRP Channel)

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28 pages, 2215 KiB

Open AccessReview

Role of TRP Channels in Liver-Related Diseases

by Yusheng Liu, Yihan Lyu, Lijuan Zhu and Hongmei Wang

Int. J. Mol. Sci. 2023, 24(15), 12509; https://doi.org/10.3390/ijms241512509 - 7 Aug 2023

Cited by 2 | Viewed by 2203

Abstract

The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). [...] Read more.

The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver’s normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases. Full article

(This article belongs to the Special Issue TRP Channel)

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15 pages, 346 KiB

Open AccessReview

TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids

by Kathleen Louis-Gray, Srinivasan Tupal and Louis S. Premkumar

Int. J. Mol. Sci. 2022, 23(17), 10016; https://doi.org/10.3390/ijms231710016 - 2 Sep 2022

Cited by 21 | Viewed by 4946

Abstract

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, [...] Read more.

The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive/nociceptive and antiemetic/emetic effects involving the peripheral, spinal, and supraspinal structures. Full article

(This article belongs to the Special Issue TRP Channel)

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