TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect Gq/11-Gi/o coincidence signals of variable strengths.

Transient receptor potential canonical 4 (TRPC4) is a receptor-operated cation channel codependent on both the Gq/11­phospholipase C signaling pathway and Gi/o proteins for activation. This makes TRPC4 an excellent coincidence sensor of neurotransmission through Gq/11- and Gi/o-coupled receptors. In whole-cell slice recordings of lateral septal neurons, TRPC4 mediates a strong depolarizing plateau that shuts down action potential firing, which may or may not be followed by a hyperpolarization that extends the firing pause to varying durations depending on the strength of Gi/o stimulation. We show that the depolarizing plateau is codependent on Gq/11-coupled group I metabotropic glutamate receptors and on Gi/o-coupled γ-aminobutyric acid type B receptors. The hyperpolarization is mediated by Gi/o activation of G protein­activated inwardly rectifying K+ (GIRK) channels. Moreover, the firing patterns, elicited by either electrical stimulation or receptor agonists, encode information about the relative strengths of Gq/11 and Gi/o inputs in the following fashion. Pure Gq/11 input produces weak depolarization accompanied by firing acceleration, whereas pure Gi/o input causes hyperpolarization that pauses firing. Although coincident Gq/11­Gi/o inputs also pause firing, the pause is preceded by a burst, and both the pause duration and firing recovery patterns reflect the relative strengths of Gq/11 versus Gi/o inputs. Computer simulations demonstrate that different combinations of TRPC4 and GIRK conductances are sufficient to produce the range of firing patterns observed experimentally. Thus, concurrent neurotransmission through the Gq/11 and Gi/o pathways is converted to discernible electrical responses by the joint actions of TRPC4 and GIRK for communication to downstream neurons.

Restoring light sensitivity using tunable near-infrared sensors.

Enabling near-infrared light sensitivity in a blind human retina may supplement or restore visual function in patients with regional retinal degeneration. We induced near-infrared light sensitivity using gold nanorods bound to temperature-sensitive engineered transient receptor potential (TRP) channels. We expressed mammalian or snake TRP channels in light-insensitive retinal cones in a mouse model of retinal degeneration. Near-infrared stimulation increased activity in cones, ganglion cell layer neurons, and cortical neurons, and enabled mice to perform a learned light-driven behavior. We tuned responses to different wavelengths, by using nanorods of different lengths, and to different radiant powers, by using engineered channels with different temperature thresholds. We targeted TRP channels to human retinas, which allowed the postmortem activation of different cell types by near-infrared light.

Transient receptor potential canonical 5 channel is involved in the cardiac damage related to obstructive sleep apnea-hypopnea syndrome in rats.

BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is recognized as an independent risk factor of cardiovascular disease. The release of Ca2+ mediated by transient receptor potential canonical (TRPC) channels participates in the hypoxia-induced pathophysiological changes in the cardiovascular systems in case of OSAHS. This study aimed to investigate which subtypes of TRPCs were involved in OSAHS in a rat model of intermittent hypoxia. METHODS: OSAHS was induced by exposure of rats to intermittent hypoxia. The expression of TRPCrelated genes and proteins in the cardiomyocytes by qRT-PCR and Western Blotting, respectively. RESULTS: The mRNA expression of TRPC3/TRPC4/TRPC5 increased significantly in OSAHS group compared with the control group (P<0.05). The TRPC5 protein expression was significantly higher in the OSAHS control than the control group (P<0.05). CONCLUSIONS: The TRPC5 channel is likely to be involved in the OSAHS induced pathophysiological changes in the myocardium and may become a target to prevent OSAHS related cardiac damage.

Sensory Neuron-Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice.

Psoriasis is an inflammatory skin disease associated with itch, which is a troublesome symptom with a few therapeutic options. TRPC4 is highly expressed in dorsal root ganglia (DRGs). Recently, we have revealed itch signaling in DRG neurons by which TRPC4 mediates itch to serotonergic antidepressants and demonstrated the antipruritic effect of the TRPC4 inhibitor ML204. However, the role of TRPC4 in acute and chronic itch is still largely unknown. Here, we have characterized the expression of TRPC4 in peptidergic DRG neurons and showed that acute itch induced by serotonin and histamine was attenuated in Trpc4-knockout mice and ML204-treated mice. We have also shown that silencing TRPC4 in DRG and its inhibition by intradermal injections were also effective in decreasing psoriatic itch after the repeated application of imiquimod, which is a preclinical model of psoriasis. Of clinical relevance, intradermal injections of ML204 in psoriasiform skin significantly reversed imiquimod-established chronic itch and cutaneous inflammation. Given that TRPC4 is expressed in human DRGs and a specific inhibitor is in clinical trials, our data not only expand our understanding of itch and psoriasis, but also reveal TRPC4 as a potential therapeutic target with considerable translational benefits.

TRPC channels: Structure, function, regulation and recent advances in small molecular probes.

Transient receptor potential canonical (TRPC) channels constitute a group of receptor-operated calcium-permeable nonselective cation channels of the TRP superfamily. The seven mammalian TRPC members, which can be further divided into four subgroups (TRPC1, TRPC2, TRPC4/5, and TRPC3/6/7) based on their amino acid sequences and functional similarities, contribute to a broad spectrum of cellular functions and physiological roles. Studies have revealed complexity of their regulation involving several components of the phospholipase C pathway, Gi and Go proteins, and internal Ca2+ stores. Recent advances in cryogenic electron microscopy have provided several high-resolution structures of TRPC channels. Growing evidence demonstrates the involvement of TRPC channels in diseases, particularly the link between genetic mutations of TRPC6 and familial focal segmental glomerulosclerosis. Because TRPCs were discovered by the molecular identity first, their pharmacology had lagged behind. This is rapidly changing in recent years owning to great efforts from both academia and industry. A number of potent tool compounds from both synthetic and natural products that selective target different subtypes of TRPC channels have been discovered, including some preclinical drug candidates. This review will cover recent advancements in the understanding of TRPC channel regulation, structure, and discovery of novel TRPC small molecular probes over the past few years, with the goal of facilitating drug discovery for the study of TRPCs and therapeutic development.

TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons.

The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked for major differences in dendritic morphology in neurons from TRPC1+/+ and TRPC1-/- mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau potential was increased in TRPC1-/- mice. There was also a small increase in the minor population of CA1 neurons that have more than one apical dendrite in TRPC1-/- mice. We conclude that TRPC1 has an inhibitory effect on receptor-operated nonselective cation channels in hippocampal CA1 neurons probably as a result of heterotetramer formation with other TRPC isoforms, and that TRPC1 deletion has only minor effects on dendritic morphology.

TRPC1 mediates slow excitatory synaptic transmission in hippocampal oriens/alveus interneurons.

Hippocampal GABAergic interneurons play key roles in regulating principal cell activity and plasticity. Interneurons located in stratum oriens/alveus (O/A INs) receive excitatory inputs from CA1 pyramidal cells and express a Hebbian form of long-term potentiation (LTP) at their excitatory input synapses. This LTP requires the activation of metabotropic glutamate receptors 1a (mGluR1a) and Ca2+ entry via transient receptor potential (TRP) channels. However, the type of TRP channels involved in synaptic transmission at these synapses remains largely unknown. Using patch-clamp recordings, we show that slow excitatory postsynaptic currents (EPSCs) evoked in O/A INs are dependent on TRP channels but may be independent of phospholipase C. Using reverse transcription polymerase chain reaction (RT-PCR) we found that mRNA for TRPC 1, 3-7 was present in CA1 hippocampus. Using single-cell RT-PCR, we found expression of mRNA for TRPC 1, 4-7, but not TRPC3, in O/A INs. Using co-immunoprecipitation assays in HEK-293 cell expression system, we found that TRPC1 and TRPC4 interacted with mGluR1a. Co-immunoprecipitation in hippocampus showed that TRPC1 interacted with mGluR1a. Using immunofluorescence, we found that TRPC1 co-localized with mGluR1a in O/A IN dendrites, whereas TRPC4 localization appeared limited to O/A IN cell body. Down-regulation of TRPC1, but not TRPC4, expression in O/A INs using small interfering RNAs prevented slow EPSCs, suggesting that TRPC1 is an obligatory TRPC subunit for these EPSCs. Our findings uncover a functional role of TRPC1 in mGluR1a-mediated slow excitatory synaptic transmission onto O/A INs that could be involved in Hebbian LTP at these synapses.

TRPC Channels in Proteinuric Kidney Diseases.

Over a decade ago, mutations in the gene encoding TRPC6 (transient receptor potential cation channel, subfamily C, member 6) were linked to development of familial forms of nephrosis. Since this discovery, TRPC6 has been implicated in the pathophysiology of non-genetic forms of kidney disease including focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, immune-mediated kidney diseases, and renal fibrosis. On the basis of these findings, TRPC6 has become an important target for the development of therapeutic agents to treat diverse kidney diseases. Although TRPC6 has been a major focus for drug discovery, more recent studies suggest that other TRPC family members play a role in the pathogenesis of glomerular disease processes and chronic kidney disease (CKD). This review highlights the data implicating TRPC6 and other TRPC family members in both genetic and non-genetic forms of kidney disease, focusing on TRPC3, TRPC5, and TRPC6 in a cell type (glomerular podocytes) that plays a key role in proteinuric kidney diseases.

Loss of Ca2+ entry via Orai-TRPC1 induces ER stress, initiating immune activation in macrophages.

Activation of cellular stresses is associated with inflammation; however, the mechanisms are not well identified. Here, we provide evidence that loss of Ca2+ influx induces endoplasmic reticulum (ER) stress in primary macrophages and in murine macrophage cell line Raw 264.7, in which the unfolded protein response is initiated to modulate cytokine production, thereby activating the immune response. Stressors that initiate the ER stress response block store-dependent Ca2+ entry in macrophages prior to the activation of the unfolded protein response. The endogenous Ca2+ entry channel is dependent on the Orai1-TRPC1-STIM1 complex, and the presence of ER stressors decreased expression of TRPC1, Orai1 and STIM1. Additionally, blocking Ca2+ entry with SKF96365 also induced ER stress, promoted cytokine production, activation of autophagy, increased caspase activation and induced apoptosis. Furthermore, ER stress inducers inhibited cell cycle progression, promoted the inflammatory M1 phenotype, and increased phagocytosis. Mechanistically, restoration of Orai1-STIM1 expression inhibited the ER stress-mediated loss of Ca2+ entry that prevents ER stress and inhibits cytokine production, and thus induced cell survival. These results suggest an unequivocal role of Ca2+ entry in modulating ER stress and in the induction of inflammation.

TRPC channels regulate Ca2+-signaling and short-term plasticity of fast glutamatergic synapses.

Transient receptor potential (TRP) proteins form Ca2+-permeable, nonselective cation channels, but their role in neuronal Ca2+ homeostasis is elusive. In the present paper, we show that TRPC channels potently regulate synaptic plasticity by changing the presynaptic Ca2+-homeostasis of hippocampal neurons. Specifically, loss of TRPC1/C4/C5 channels decreases basal-evoked secretion, reduces the pool size of readily releasable vesicles, and accelerates synaptic depression during high-frequency stimulation (HFS). In contrast, primary TRPC5 channel-expressing neurons, identified by a novel TRPC5-τ-green fluorescent protein (τGFP) knockin mouse line, show strong short-term enhancement (STE) of synaptic signaling during HFS, indicating a key role of TRPC5 in short-term plasticity. Lentiviral expression of either TRPC1 or TRPC5 turns classic synaptic depression of wild-type neurons into STE, demonstrating that TRPCs are instrumental in regulating synaptic plasticity. Presynaptic Ca2+ imaging shows that TRPC activity strongly boosts synaptic Ca2+ dynamics, showing that TRPC channels provide an additional presynaptic Ca2+ entry pathway, which efficiently regulates synaptic strength and plasticity.

Combined bone marrow stromal cells and oxiracetam treatments ameliorates acute cerebral ischemia/reperfusion injury through TRPC6.

Ischemic stroke has become one of the leading causes of deaths and disabilities all over the world. In this study, we investigated the therapeutic effects of combined bone marrow stromal cells (BMSCs) and oxiracetam treatments on acute cerebral ischemia/reperfusion (I/R) injury. A rat model of middle cerebral artery occlusion (MCAO) followed by complete reperfusion, as well as a cortex neuron oxygen-glucose deprivation (OGD) model was established. When compared with BMSCs or oxiracetam monotherapy, combination therapy significantly improved functional restoration with decreased infarct volume in observed ischemic brain. We propose that it may occur through the transient receptor potential canonical (TRPC)6 neuron survival pathway. The increased expression of TRPC6 along with the reduction of neuronal cell death in the OGD cortex neurons and combination therapy group indicated that the TRPC6 neuron survival pathway plays an important role in the combined BMSCs and oxiracetam treatments. We further tested the activity of the calpain proteolytic system, and the results suggested that oxiracetam could protect the integrity of TRPC6 neuron survival pathway by inhibiting TRPC6 degradation. The protein levels of phospho-cAMP response element binding protein (p-CREB) were tested. It was found that BMSCs play a role in the activation of the TRPC6 pathway. Our study suggests that the TRPC6 neuron survival pathway plays a significant role in the protective effect of combined BMSCs and oxiracetam treatments on acute cerebral I/R injury. Combined therapy could inhibit the abnormal degradation of TRPC6 via decreasing the activity of calpain and increasing the activation of TRPC6 neuron survival pathway.

Role of TRPC1 channels in pressure-mediated activation of airway remodeling.

BACKGROUND: Bronchoconstriction and cough, a characteristic of the asthmatic response, leads to development of compressive stresses in the airway wall. We hypothesized that progressively pathological high mechanical stress could act on mechanosensitive cation channels, such as transient receptor potential channel 1 (TRPC1) and then contributes to airway remodeling. METHODS: We imitate the pathological airway pressure in vitro using cyclic stretch at 10 and 15% elongation. Ca2+ imaging was applied to measure the activity of TRPC1 after bronchial epithelial cells exposed to cyclic stretch for 0, 0.5, 1, 1.5, 2, 2.5 h. To further clarify the function of channnel TRPC1 in the process of mechano-transduction in airway remodeling, the experiment in vivo was implemented. The TRPC1 siRNA and budesonide were applied separately to asthmatic models. The morphological changes were measured by HE and Massion method. The expression levels of TRPC1 were evaluated by real-time PCR, western blot and immunohistochemistry. The protein expression level of IL-13, TGF-ß1 and MMP-9 in BALF were measured by ELISA. RESULTS: The result showed that cyclic stretch for 15% elongation at 1.5 h could maximize the activity of TRPC1 channel. This influx in Ca2+ was blocked by TRPC1 siRNA. Higher TRPC1 expression was observed in the bronchial epithelial layer of ovalbumin induced asthmatic models. The knockdown of TRPC1 with TRPC1 siRNA was associated with a hampered airway remodeling process, such as decreased bronchial wall thickness and smooth muscle hypertrophy/hyperplasia, a decreased ECM deposition area and inflammation infiltration around airway wall. Meantime, expression of IL-13, TGF-ß1 and MMP-9 in OVA+TRPC1 siRNA also showed reduced level. TRPC1 intervention treatment showed similar anti-remodeling therapeutic effect with budesonide. CONCLUSIONS: These results demonstrate that most TRPC1 channels expressed in bronchial epithelial cells mediate the mechanotransduction mechanism. TRPC1 inducing abnormal Ca2+ signal mediates receptor-stimulated and mechanical stimulus-induced airway remodeling. The inhibition of TRPC1 channel could produce similar therapeutic effect as glucocortisteroid to curb the development of asthmatic airway remodeling.

TRPC channels are not required for graded persistent activity in entorhinal cortex neurons.

Adaptive behavior requires the transient storage of information beyond the physical presence of external stimuli. This short-lasting form of memory involves sustained ("persistent") neuronal firing which may be generated by cell-autonomous biophysical properties of neurons or/and neural circuit dynamics. A number of studies from brain slices reports intrinsically generated persistent firing in cortical excitatory neurons following suprathreshold depolarization by intracellular current injection. In layer V (LV) neurons of the medial entorhinal cortex (mEC) persistent firing depends on the activation of cholinergic muscarinic receptors and is mediated by a calcium-activated nonselective cation current (ICAN ). The molecular identity of this conductance remains, however, unknown. Recently, it has been suggested that the underlying ion channels belong to the canonical transient receptor potential (TRPC) channel family and include heterotetramers of TRPC1/5, TRPC1/4, and/or TRPC1/4/5 channels. While this suggestion was based on pharmacological experiments and on effects of TRP-interacting peptides, an unambiguous proof based on TRPC channel-depleted animals is pending. Here, we used two different lines of TRPC channel knockout mice, either lacking TRPC1-, TRPC4-, and TRPC5-containing channels or lacking all seven members of the TRPC family. We report unchanged persistent activity in mEC LV neurons in these animals, ruling out that muscarinic-dependent persistent activity depends on TRPC channels.

Mitochondrial TRPC3 promotes cell proliferation by regulating the mitochondrial calcium and metabolism in renal polycystin-2 knockdown cells.

PURPOSE: Previous studies indicate that autosomal dominant polycystic kidney disease (ADPKD) cells exhibited dysregulated calcium homeostasis and enhanced cell proliferation. TRPC3 has been shown to function in the modulation of calcium and sodium entry, but whether TRPC3 plays a role in cellular abnormalities of ADPKD cells has not been defined. METHODS: Human conditionally immortalized proximal tubular epithelial cells and mouse IMCD3 cells were used with polycystin-2 (PC2, TRPP2) knockdown. Cell proliferation assay was used to detect the cell proliferations upon different treatments. QRT-PCR and western blotting were used to measure the expression profiles of TRPP2 and other proteins. High-resolution respirometry, enzymic activities and ROS levels were detected to reflect the mitochondrial functions. Calcium and sodium uptakes were measured using Fura2-AM and SBFI dyes. RESULTS: We showed that PC2 knockdown promoted cell proliferation, ROS productions and ERK phosphorylation, compared with negative control. Meanwhile, we demonstrated that receptor-operated calcium entry (ROCE) exhibited less reductions compared with store-operated calcium entry (SOCE) upon PC2 knockdown. Inhibition of ROCE and SOCE by specific inhibitors partially reversed the enhanced cell proliferation, ROS productions and ERK phosphorylation induced by PC2 knockdown. Moreover, TRPC3 upregulation was observed upon PC2 knockdown, which acted as both SOC and ROC, promoting cation entry, cell proliferation and ERK phosphorylation. Furthermore, we showed that mitochondrial located TRPC3 was upregulated and modulating mitochondrial calcium uptake, thus promoting the ROS productions in the presence of PC2 knockdown. CONCLUSIONS: We demonstrated that TRPC3 upregulation upon PC2 knockdown aggravated the mitochondrial abnormalities and cell proliferation by modulating mitochondrial calcium uptake. Targeting TRPC3 might be a promising target for ADPKD treatment.

Treasure troves of pharmacological tools to study transient receptor potential canonical 1/4/5 channels.

Canonical or classical transient receptor potential 4 and 5 proteins (TRPC4 and TRPC5) assemble as homomers or heteromerize with TRPC1 protein to form functional nonselective cationic channels with high calcium permeability. These channel complexes, TRPC1/4/5, are widely expressed in nervous and cardiovascular systems, also in other human tissues and cell types. It is debatable that TRPC1 protein is able to form a functional ion channel on its own. A recent explosion of molecular information about TRPC1/4/5 has emerged including knowledge of their distribution, function, and regulation suggesting these three members of the TRPC subfamily of TRP channels play crucial roles in human physiology and pathology. Therefore, these ion channels represent potential drug targets for cancer, epilepsy, anxiety, pain, and cardiac remodelling. In recent years, a number of highly selective small-molecule modulators of TRPC1/4/5 channels have been identified as being potent with improved pharmacological properties. This review will focus on recent remarkable small-molecule agonists: (-)-englerin A and tonantzitlolone and antagonists: Pico145 and HC7090, of TPRC1/4/5 channels. In addition, this work highlights other recently identified modulators of these channels such as the benzothiadiazine derivative, riluzole, ML204, clemizole, and AC1903. Together, these treasure troves of agonists and antagonists of TRPC1/4/5 channels provide valuable hints to comprehend the functional importance of these ion channels in native cells and in vivo animal models. Importantly, human diseases and disorders mediated by these proteins can be studied using these compounds to perhaps initiate drug discovery efforts to develop novel therapeutic agents.

TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling.

Airway remodeling with progressive epithelial alterations in the respiratory tract is a severe consequence of asthma. Although dysfunctional signaling transduction is attributed to airway inflammation, the exact mechanism of airway remodeling remains largely unknown. TRPC1, a member of the transient receptor potential canonical Ca2+ channel family, possesses versatile functions but its role in airway remodeling remains undefined. Here, we show that ablation of TRPC1 in mice alleviates airway remodeling following house dust mite (HDM) challenge with decreases in mucus production, cytokine secretion, and collagen deposition. HDM challenge induces Ca2+ influx via the TRPC1 channel, resulting in increased levels of signal transducer and activator of transcription 3 (STAT3) and proinflammatory cytokines. In contrast, STAT3 expression was significantly decreased in TRPC1-/- mouse lungs compared with wild-type controls after HDM challenge. Mechanistically, STAT3 promotes epithelial-to-mesenchymal transition and increases mucin 5AC expression. Collectively, these findings identify TRPC1 as a modulator of HDM-induced airway remodeling via STAT3-mediated increase in mucus production, which provide new insight in our understanding of the molecular basis of airway remodeling, and identify novel therapeutic targets for intervention of severe chronic asthma.-Pu, Q., Zhao, Y., Sun, Y., Huang, T., Lin, P., Zhou, C., Qin, S., Singh, B. B., Wu, M. TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling.

Reduced expression but not deficiency of GFI1 causes a fatal myeloproliferative disease in mice.

Growth factor independent 1 (Gfi1) controls myeloid differentiation by regulating gene expression and limits the activation of p53 by facilitating its de-methylation at Lysine 372. In human myeloid leukemia, low GFI1 levels correlate with an inferior prognosis. Here, we show that knockdown (KD) of Gfi1 in mice causes a fatal myeloproliferative disease (MPN) that could progress to leukemia after additional mutations. Both KO and KD mice accumulate myeloid cells that show signs of metabolic stress and high levels of reactive oxygen species. However, only KO cells have elevated levels of Lysine 372 methylated p53. This suggests that in contrast to absence of GFI1, KD of GFI1 leads to the accumulation of myeloid cells because sufficient amount of GFI1 is present to impede p53-mediated cell death, leading to a fatal MPN. The combination of myeloid accumulation and the ability to counteract p53 activity under metabolic stress could explain the role of reduced GF1 expression in human myeloid leukemia.

Structure-Function Relationship and Physiological Roles of Transient Receptor Potential Canonical (TRPC) 4 and 5 Channels.

The study of the structure-function relationship of ion channels has been one of the most challenging goals in contemporary physiology. Revelation of the three-dimensional (3D) structure of ion channels has facilitated our understanding of many of the submolecular mechanisms inside ion channels, such as selective permeability, voltage dependency, agonist binding, and inter-subunit multimerization. Identifying the structure-function relationship of the ion channels is clinically important as well since only such knowledge can imbue potential therapeutics with practical possibilities. In a sense, recent advances in the understanding of the structure-relationship of transient receptor potential canonical (TRPC) channels look promising since human TRPC channels are calcium-permeable, non-selective cation channels expressed in many tissues such as the gastrointestinal (GI) tract, kidney, heart, vasculature, and brain. TRPC channels are known to regulate GI contractility and motility, pulmonary hypertension, right ventricular hypertrophy, podocyte injury, seizure, fear, anxiety-like behavior, and many others. In this article, we tried to elaborate recent findings of Cryo-EM (cryogenic-electron microscopy) based structural information of TRPC 4 and 5 channels and domain-specific functions of the channel, such as G-protein mediated activation mechanism, extracellular modification of the channel, homo/hetero-tetramerization, and pharmacological gating mechanisms.

[New Strategies for Exercise-Mimetic Medication].

　Moderate exercise has been reported to combat several diseases, including cardiovascular diseases and depressants. However, many patients do not have ability to undergo exercise therapy due to aging and severity of the symptoms. Therefore development of new drugs that can imitate exercise therapy is desired and actually studied worldwide. The heart is one of the physical load-responsive target organs such as skeletal muscles and vascular smooth muscles. The heart can adapt from environmental stress by changing its structure and morphology (i.e., remodeling). Physiological remodeling, caused by exercise or pregnancy, can be defined by compensative and reversible changes to the heart, whereas pathological remodeling can be defined by irreversible changes of the heart, through aberrant calcium ion (Ca2+) signaling as well as production of reactive oxygen species (ROS). However, crosstalk between Ca2+ and ROS remains obscure. In this review we will introduce our recent findings on the functional crosstalk between transient receptor potential canonical (TRPC) 3 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) 2 as a novel molecular target to mimic exercise therapy.

Canonical transient receptor potential 3 channels in atrial fibrillation.

The pathogenesis of atrial fibrillation (AF) is largely dependent on structural remodeling and electrical reconfiguration, which in turn drive localized fibrosis. Canonical transient receptor potential 3 (TRPC3) channel is indispensable regulator of fibrosis development, promoting fibroblasts to transition into myofibroblasts via intracellular Ca2+ overload. TRPC3 is a non-voltage gated, non-selective cation channel that regulates the permeability of the cell to Ca2+. When subjected to various external physical and chemical stimuli, such as angiotensin II (AngII), mechanical stretch, hypoxia, or oxidative stress, TRPC3 coordinates with downstream signal transduction pathways to alter gene expression and thereby regulate a number of distinct pathological patterns and mechanisms. This review will focus on how TRPC3 affects AF pathogenesis by exploring the underlying mechanisms governing fibrosis associated with particular signaling proteins, ultimately highlighting the characteristics of TPRC3 that mark it as a novel therapeutic target for AF alleviation.