TRPC3: A New Target for Therapeutic Strategies in Chronic Pain−DAG-mediated Activation of Non-selective Cation Currents and Chronic Pain (Mol Pain 2014;10:43)

Meng, Xia; Liú, Dan; Yao, Chun Hsu

doi:10.5056/jnm15078

Cited by 7 publications

(7 citation statements)

References 10 publications

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“…We focused on the synaptogenesis pathway in particular, as it includes several genes present in overlapping canonical pathways, including changes in receptors involved in organization of excitatory signaling (Ephb) and synapses which may be involved in development of chronic pain (TrkB and BDNF). We validated receptors for significant genes in the synaptogenesis pathway, and genes considered possible contributors to pain that also showed significant differences between conditions Gabrg3, Il6st, Kcng3, Piezo2, Scn5a, Trpc3;Waxman et al, 1999;Wickenden, 2002;De Jongh et al, 2003;Devor, 2006;Eijkelkamp et al, 2013;Guptarak et al, 2013;Xia et al, 2015;Deng et al, 2018;Szczot et al, 2018). Additional targets were chosen in order to validate isolation of the correct cell population (Scn10a).…”

Section: Validation Of Rnaseq Data Using Qpcrmentioning

confidence: 99%

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Yasko

Moss

Mains

2019

Front. Mol. Neurosci.

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Traumatic spinal cord injury (SCI) has devastating implications for patients, including a high predisposition for developing chronic pain distal to the site of injury. Chronic pain develops weeks to months after injury, consequently, patients are treated after irreparable changes have occurred. Nociceptors are central to chronic pain; however, the diversity of this cellular population presents challenges to understanding mechanisms and attributing pain modalities to specific cell types. To begin to address how peripheral sensory neurons below the injury level may contribute to the below-level pain reported by SCI patients, we examined SCI-induced changes in gene expression in lumbar dorsal root ganglia (DRG) below the site of injury. SCI was performed at the T10 vertebral level, with injury produced by a vessel clip with a closing pressure of 15 g for 1 min. Alterations in gene expression produce long-term sensory changes, therefore, we were interested in studying SCI-induced transcripts before the onset of chronic pain, which may trigger changes in downstream signaling pathways and ultimately facilitate the transmission of pain. To examine changes in the nociceptor subpopulation in DRG distal to the site of injury, we retrograde labeled sensory neurons projecting to the hairy hindpaw skin with fluorescent dye and collected the corresponding lumbar (L2-L6) DRG 4 days post-injury. Following dissociation, labeled neurons were purified by fluorescenceactivated cell sorting (FACS). RNA was extracted from sorted sensory neurons of naïve, sham, or SCI mice and sequenced. Transcript abundances validated that the desired population of nociceptors were isolated. Cross-comparisons to data sets from similar studies confirmed, we were able to isolate our cells of interest and identify a unique pattern of gene expression within a subpopulation of neurons projecting to the hairy hindpaw skin. Differential gene expression analysis showed high expression levels and significant transcript changes 4 days post-injury in SCI cell populations relevant to the onset of chronic pain. Regulatory interrelationships predicted by pathway analysis implicated changes within the synaptogenesis signaling pathway as well as networks related to inflammatory signaling mechanisms, suggesting a role for synaptic plasticity and a correlation with pro-inflammatory signaling in the transition from acute to chronic pain.

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Section: Validation Of Rnaseq Data Using Qpcrmentioning

confidence: 99%

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Yasko

Moss

Mains

2019

Front. Mol. Neurosci.

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“…Dysfunction of TRPC3 has been linked to neurodegenerative disease, cardiac hypertrophy, and ovarian adenocarcinoma ( Becker et al, 2011 ; Kitajima et al, 2016 ; Yang et al, 2009 ). Although TRPC3 has wide pharmaceutical applications in treatment of these diseases, drug development specifically targeting TRPC3 has been limited due to the lack of understanding of its molecular activation mechanisms ( Oda et al, 2017 ; Xia et al, 2015 ). Here, we report the structure of full-length human TRPC3 (hTRPC3) in a lipid-occupied, inactive state at an atomic resolution of 3.3 Å using single-particle cryo-electron microscopy (cryo-EM).…”

Section: Introductionmentioning

confidence: 99%

Structure of the human lipid-gated cation channel TRPC3

Chen

Choi

Sun

et al. 2018

eLife

115

134

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The TRPC channels are crucially involved in store-operated calcium entry and calcium homeostasis, and they are implicated in human diseases such as neurodegenerative disease, cardiac hypertrophy, and spinocerebellar ataxia. We present a structure of the full-length human TRPC3, a lipid-gated TRPC member, in a lipid-occupied, closed state at 3.3 Angstrom. TRPC3 has four elbow-like membrane reentrant helices prior to the first transmembrane helix. The TRP helix is perpendicular to, and thus disengaged from, the pore-lining S6, suggesting a different gating mechanism from other TRP subfamily channels. The third transmembrane helix S3 is remarkably long, shaping a unique transmembrane domain, and constituting an extracellular domain that may serve as a sensor of external stimuli. We identified two lipid-binding sites, one being sandwiched between the pre-S1 elbow and the S4-S5 linker, and the other being close to the ion-conducting pore, where the conserved LWF motif of the TRPC family is located.

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“…This suggests that the high TRPC3 expression in the peripheral nerves or an increase in the T allele number was associated with the higher risk of chronic pain in the present study. In the thoracolumbar DRGs in rats, the prolonged elevations of intracellular calcium can cause neuronal hyperexcitability and hypersensitivity, leading to nociception and chronic pain [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…The TRPC3 channels, as well as other TRP channels (e.g., TRPV1, TRPV3, TRPV4, TRPA1, TRPM3, and TRPM8), possibly play an important role in nociception [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 26 ]. In humans, TRPC3 mRNA is highly expressed in the brain, including the cervical spinal cord and heart [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…This unique dual contribution to SOCE and ROCE defines the calcium-permeable TRPC, including TRPC3, as a key regulator of the calcium homeostasis in the dorsal root ganglia (DRGs) neurons under normal and pathological pain conditions. Xia et al (2015) suggested that TRPC3 may be a novel therapeutic target for chronic pain [ 26 ]. We previously reported that a SNP near the TRPC3 gene was associated with the postoperative fentanyl requirements and pain [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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

Aoki

Nishizawa

Ohka

et al. 2023

IJMS

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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.

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TRPC3: A New Target for Therapeutic Strategies in Chronic Pain−DAG-mediated Activation of Non-selective Cation Currents and Chronic Pain (Mol Pain 2014;10:43)

Cited by 7 publications

References 10 publications

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Transcriptional Profiling of Non-injured Nociceptors After Spinal Cord Injury Reveals Diverse Molecular Changes

Structure of the human lipid-gated cation channel TRPC3

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

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