scholarly journals TRPC channels blockade abolishes septic cardiac dysfunction by hampering intracellular inflammation and Ca2+ leakage

2021 ◽  
Author(s):  
Wei Cao ◽  
Na Tang ◽  
Wen Tian ◽  
Guang-Yuan Ma ◽  
Xiong Xiao ◽  
...  
Keyword(s):  
Heart Failure ◽  
Endoplasmic Reticulum ◽  
Cardiac Dysfunction ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Regulatory Modules ◽  
Novel Approach ◽  
Intracellular Ca ◽  
Transient Receptor

Abstract Intracellular Ca2+ dysregulation is a key marker in septic cardiac dysfunction; however, regulation of the classic Ca2+ regulatory modules cannot successfully abolish this symptom. The present study shows that the knockout of transient receptor potential canonical (TRPC) channel isoforms, TRPC1 and TRPC6, can strikingly ameliorate LPS-challenged heart failure and prolong survivability in mice. The LPS-triggered Ca2+ release from the endoplasmic reticulum both in cardiomyocytes and macrophages is significantly inhibited by Trpc1 or Trpc6 knockout. Meanwhile, TRPC’s molecular partner, calmodulin is uncoupled during Trpc1 or Trpc6 deficiency and binds to TLR4’s Pococurante site and atypical isoleucine-glutamine-like motif to block the inflammation cascade. Importantly, blocking the C-terminal CaM/IP3R binding domain in TRPC with chemical inhibitor could markedly obstruct the Ca2+ leak and TLR4-mediated inflammation burst, demonstrating a powerful cardioprotective effect in endotoxemia and polymicrobial sepsis. Our findings provide new insights into the pathogenesis of septic cardiac dysfunction and suggest a novel approach for its treatment.

scholarly journals TRPC5-CaV3 complex mediates Leptin-induced excitability in hypothalamic neurons

2020 ◽  
Author(s):  
Paula P. Perissinotti ◽  
Elizabeth Martínez-Hernández ◽  
Erika S. Piedras-Rentería
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Membrane Depolarization ◽  
Macromolecular Complex ◽  
Trpc Channels ◽  
Neuron Excitability ◽  
Intracellular Ca ◽  
Transient Receptor

ABSTRACTLeptin regulates hypothalamic POMC+ (pro-opiomelanocortin) neurons by inducing TRPC (Transient Receptor Potential Cation) channel-mediate membrane depolarization. Here we assessed the role of T-type channels on POMC neuron excitability and leptin-induced depolarization in vitro. We demonstrate T-type currents are indispensable for both processes, as treatment with NNC-55-0396 prevented the membrane depolarization and rheobase changes induced by leptin in cultured mouse POMC neurons. Furthermore, we demonstrate TRPC1/C5 channels and CaV3.1 and CaV3.2 channels co-exist in complex. The functional relevance of this complex was corroborated using intracellular Ca2+ chelators; intracellular BAPTA (but not EGTA) application was sufficient to preclude POMC neuron excitability by preventing leptin-induced calcium influx through TRPC channels and T-type channel function.We conclude T-type channels are integral in POMC neuron excitability. Leptin activation of TRPC channels existing in a macromolecular complex with T-type channels recruits the latter by locally-induced membrane depolarization, further depolarizing POMC neurons, triggering action potentials and excitability.

scholarly journals BDNF Induces Calcium Elevations Associated With IBDNF, a Nonselective Cationic Current Mediated by TRPC Channels

2007 ◽  
Vol 98 (4) ◽  
pp. 2476-2482 ◽  
Author(s):  
Michelle D. Amaral ◽  
Lucas Pozzo-Miller
Keyword(s):  
Hippocampal Neurons ◽  
Transient Receptor Potential ◽  
Pyramidal Neurons ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Hippocampal Pyramidal Neurons ◽  
Cationic Current ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
Nonselective Cationic Current

Brain-derived neurotrophic factor (BDNF) has potent actions on hippocampal neurons, but the mechanisms that initiate its effects are poorly understood. We report here that localized BDNF application to apical dendrites of CA1 pyramidal neurons evoked transient elevations in intracellular Ca2+ concentration, which are independent of membrane depolarization and activation of N-methyl-d-aspartate receptors (NMDAR). These Ca2+ signals were always associated with IBDNF, a slow and sustained nonselective cationic current mediated by transient receptor potential canonical (TRPC3) channels. BDNF-induced Ca2+ elevations required functional Trk and inositol-tris-phosphate (IP3) receptors, full intracellular Ca2+ stores as well as extracellular Ca2+, suggesting the involvement of TRPC channels. Indeed, the TRPC channel inhibitor SKF-96365 prevented BDNF-induced Ca2+ elevations and the associated IBDNF. Thus TRPC channels emerge as novel mediators of BDNF-induced intracellular Ca2+ elevations associated with sustained cationic membrane currents in hippocampal pyramidal neurons.

scholarly journals Satellite glial cells in sensory ganglia express functional transient receptor potential ankyrin 1 that is sensitized in neuropathic and inflammatory pain

2020 ◽  
Vol 16 ◽  
pp. 174480692092542 ◽  
Author(s):  
Seung Min Shin ◽  
Brandon Itson-Zoske ◽  
Yongsong Cai ◽  
Chensheng Qiu ◽  
Bin Pan ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Glial Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Sensory Ganglia ◽  
Satellite Glial Cells ◽  
Intracellular Ca ◽  
Transient Receptor

Transient receptor potential ankyrin 1 (TRPA1) is well documented as an important molecule in pain hypersensitivity following inflammation and nerve injury and in many other cellular biological processes. Here, we show that TRPA1 is expressed not only by sensory neurons of the dorsal root ganglia (DRG) but also in their adjacent satellite glial cells (SGCs), as well as nonmyelinating Schwann cells. TRPA1 immunoreactivity is also detected in various cutaneous structures of sensory neuronal terminals, including small and large caliber cutaneous sensory fibers and endings. The SGC-expressed TRPA1 is functional. Like DRG neurons, dissociated SGCs exhibit a robust response to the TRPA1-selective agonist allyl isothiocyanate (AITC) by an increase of intracellular Ca2+ concentration ([Ca2+]i). These responses are abolished by the TRPA1 antagonist HC030031 and are absent in SGCs and neurons from global TRPA1 null mice. SGCs and neurons harvested from DRG proximal to painful tissue inflammation induced by plantar injection of complete Freund’s adjuvant show greater AITC-evoked elevation of [Ca2+]i and slower recovery compared to sham controls. Similar TRPA1 sensitization occurs in both SGCs and neurons during neuropathic pain induced by spared nerve injury. Together, these results show that functional TRPA1 is expressed by sensory ganglia SGCs, and TRPA1 function in SGCs is enhanced after both peripheral inflammation and nerve injury, and suggest that TRPA1 in SGCs may contribute to inflammatory and neuropathic pain.

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 The Na+/Ca2+ Exchanger Inhibitor, KB-R7943, Blocks a Nonselective Cation Channel Implicated in Chemosensory Transduction

2009 ◽  
Vol 101 (3) ◽  
pp. 1151-1159 ◽  
Author(s):  
A. Pezier ◽  
Y. V. Bobkov ◽  
B. W. Ache
Keyword(s):  
Transient Receptor Potential ◽  
Single Channel ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Dependent Manner ◽  
Open Probability ◽  
Olfactory Transduction ◽  
Voltage Dependent ◽  
Chemosensory Transduction ◽  
Transient Receptor

The mechanism(s) of olfactory transduction in invertebrates remains to be fully understood. In lobster olfactory receptor neurons (ORNs), a nonselective sodium-gated cation (SGC) channel, a presumptive transient receptor potential (TRP)C channel homolog, plays a crucial role in olfactory transduction, at least in part by amplifying the primary transduction current. To better determine the functional role of the channel, it is important to selectively block the channel independently of other elements of the transduction cascade, causing us to search for specific pharmacological blockers of the SGC channel. Given evidence that the Na+/Ca2+ exchange inhibitor, KB-R7943, blocks mammalian TRPC channels, we studied this probe as a potential blocker of the lobster SGC channel. KB-R7943 reversibly blocked the SGC current in both inside- and outside-out patch recordings in a dose- and voltage-dependent manner. KB-R7943 decreased the channel open probability without changing single channel amplitude. KB-R7943 also reversibly and in a dose-dependent manner inhibited both the odorant-evoked discharge of lobster ORNs and the odorant-evoked whole cell current. Our findings strongly imply that KB-R7943 potently blocks the lobster SGC channel and likely does so directly and not through its ability to block the Na+/Ca2+ exchanger.

scholarly journals Capacitative Ca2+ entry in agonist-induced pulmonary vasoconstriction

2001 ◽  
Vol 280 (5) ◽  
pp. L870-L880 ◽  
Author(s):  
Sharon S. McDaniel ◽  
Oleksandr Platoshyn ◽  
Jian Wang ◽  
Ying Yu ◽  
Michele Sweeney ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Channel Blocker ◽  
Receptor Potential ◽  
Rt Pcr ◽  
Pulmonary Vasoconstriction ◽  
Store Depletion ◽  
Intracellular Ca ◽  
Gene Transcripts ◽  
Transient Receptor ◽  
Sustained Increase

Agonist-induced increases in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary artery (PA) smooth muscle cells (SMCs) consist of a transient Ca2+ release from intracellular stores followed by a sustained Ca2+ influx. Depletion of intracellular Ca2+ stores triggers capacitative Ca2+ entry (CCE), which contributes to the sustained increase in [Ca2+]cyt and the refilling of Ca2+ into the stores. In isolated PAs superfused with Ca2+-free solution, phenylephrine induced a transient contraction, apparently by a rise in [Ca2+]cyt due to Ca2+ release from the intracellular stores. The transient contraction lasted for 3–4 min until the Ca2+ store was depleted. Restoration of extracellular Ca2+ in the presence of phentolamine produced a contraction potentially due to a rise in [Ca2+]cyt via CCE. The store-operated Ca2+ channel blocker Ni2+ reduced the store depletion-activated Ca2+ currents, decreased CCE, and inhibited the CCE-mediated contraction. In single PASMCs, we identified, using RT-PCR, five transient receptor potential gene transcripts. These results suggest that CCE, potentially through transient receptor potential-encoded Ca2+ channels, plays an important role in agonist-mediated PA contraction.

Abstract 296: Loss of Trpc6 Function in Cardiomyocytes Improves Survival and Attenuates Progression of Cardiac Dysfunction After Mi

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Polina Gross ◽  
Xiaoxiao Zhang ◽  
Tao Wang ◽  
Amir Toib ◽  
Markus Wallner ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Dysfunction ◽  
Cardiac Myocyte ◽  
Transient Receptor Potential ◽  
Weight Ratio ◽  
Dominant Negative ◽  
Heart Weight ◽  
Trpc Channels ◽  
Pump Function ◽  
Hypertrophic Signaling

Ischemic heart disease (IHD) commonly culminates in myocardial infarction (MI), which causes cardiac myocyte death and depressed cardiac pump function. Surviving myocytes can usually maintain pump function by increasing Ca 2+ influx and contractility. However, elevated intracellular Ca 2+ also can activate pathological hypertrophic signaling that promotes cardiac dysfunction and progression into heart failure. Ca 2+ influx through Canonical Transient Receptor Potential (TRPC) channels has been classified as a potential source of hypertrophic signaling. Specifically, TRPC6 gene expression and biological activity is significantly upregulated in cardiac myocytes after MI. Our aim was to determine if TRPC6 loss of function is cardioprotective in MI mouse model. We performed an MI study on cardiac specific dominant negative (dn) TRPC6 transgenic mice that express 3 mutated amino acids (L678A-W680A) in the pore region, which disables TRPC6 channel function. In the course of 6 weeks post MI, dnTRPC6 mice had significantly greater survival (69.2%) than wild-type (WT) mice (47.5%). Cardiac function at 2 weeks post MI was decreased to the same extent in WT and dnTRPC6 mice. Ejection fraction (EF) in WT group was 30.6% vs. 57.1% and in dnTRPC6 EF was 31% vs. 61% (MI vs. sham, respectively). The EF in dnTRPC6 mice 6 weeks post MI suggested attenuation of heart failure progression compared to WT mice (32.5% vs. 26.5%, *P=0.05). Mice in the WT group demonstrated significant elevation in end diastolic and end systolic volumes (EDV and ESV) 6 weeks post MI, while dnTRPC6 had reduced end diastolic and end systolic volumes (116μL vs. 88μL and 106μL vs. 76μL, WT vs. dnTRPC6, EDV and ESV, respectively. ***P<0.0001). Hypertrophy measures of heart weight to body weight ratio and heart weight to tibia length ratio were significantly reduced in dnTRPC6 mice 6 weeks post MI as opposed to WT mice (8.4 vs. 7.3 and 13.4 vs. 11.7, respectively *P<0.05). Hypertrophic markers of ANP, BNP and βMHC followed similar downregulation trend in the dnTRPC6 mice. In conclusion, loss of TRPC6 function slows the progression of cardiac dysfunction and cardiac remodeling in the post MI heart.

Regulation of Transient Receptor Potential Canonical 4 Activity by Phospholipase C-δ1

2020 ◽  
Author(s):  
Juyeon Ko ◽  
Jongyun Myeong ◽  
Misun Kwak ◽  
Insuk So
Keyword(s):  
Phospholipase C ◽  
Transient Receptor Potential ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Potential ◽  
Regulation Mechanism ◽  
Trpc Channels ◽  
Transient Receptor Potential Canonical ◽  
Cell Current ◽  
Transient Receptor

Abstract Transient receptor potential canonical (TRPC) channels are non-selective calcium-permeable cation channels. It is suggested that TRPC4β and TRPC5 channels are regulated by phospholipase C (PLC) signaling, and are especially maintained by phosphatidylinositol 4,5-bisphosphate (PIP2). The PLCδ subtype is the most Ca2+-sensitive form among the isozymes which cleaves phospholipids to respond to the calcium rise. In this study, we investigated the regulation mechanism of TRPC channel by Ca2+, PLCδ1 and PIP2 signaling cascades. The interaction between TRPC4β and PLCδ1 was identified through the Fӧster resonance energy transfer (FRET) and co-immunoprecipitation (Co-IP). With the electrophysiological experiments, we found that TRPC4β-bound PLCδ1 reduces the overall whole-cell current of channel. The Ca2+-via opened channel promotes the activation of PLCδ1, which subsequently decreases PIP2 level. By comparison TRPC4β activity with or without PLCδ1 using differently [Ca2+]i buffered solution, we demonstrated that PLCδ1 functions in normal condition with physiological calcium range. The negative regulation effect of PLCδ1 on TRPC4β helps to elucidate the roles of each PIP2 binding residues whether they are concerned in channel maintenance or inhibition of channel activity.

scholarly journals Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Zhi-Chuan Sun ◽  
Sui-Bin Ma ◽  
Wen-Guang Chu ◽  
Dong Jia ◽  
Ceng Luo
Keyword(s):  
Chronic Pain ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpc Channels ◽  
Canonical Transient Receptor Potential ◽  
Abnormal Increase ◽  
Pathological Pain ◽  
Transient Receptor ◽  
Underlying Mechanisms

Chronic pathological pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Despite much progress we have made in understanding chronic pain in the last decades, its underlying mechanisms remain elusive. It is assumed that abnormal increase of calcium levels in the cells is a key determinant in the transition from acute to chronic pain. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is therefore helpful towards understanding the development of chronic, pathological pain. Canonical transient receptor potential (TRPC) channels form a subfamily of nonselective cation channels, which permit the permeability of Ca2+ and Na+ into the cells. Initiation of Ca2+ entry pathways by these channels triggers the development of many physiological and pathological functions. In this review, we will focus on the functional implication of TRPC channels in nociception with the elucidation of their role in the detection of external stimuli and nociceptive hypersensitivity.

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