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Arch Pharm Res 2021 Mar 24. Epub 2021 Mar 24.

Department of Pharmacology and Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, School of Pharmacy, Fourth Military Medical University, Xi'an, China.

Canonical transient receptor potential channels (TRPCs) are nonselective, high calcium permeability cationic channels. The TRPCs family includes TRPC1, TRPC2, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7. These channels are widely expressed in the cardiovascular and nervous systems and exist in many other human tissues and cell types, playing several crucial roles in the human physiological and pathological processes. Read More

Oncol Lett 2021 Apr 21;21(4):307. Epub 2021 Feb 21.

Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, D-17475 Greifswald, Germany.

In U-2 OS and MNNG-HOS osteosarcoma cells, small interfering RNA-mediated knockdown of the angiotensin-(1-7) receptor, Mas, increases cell proliferation. Whether alterations in canonical transient receptor potential channels (TRPC) expression contribute to this effect is not clear. In the present study, a basic description of TRPC subtype expression in osteosarcoma cell lines was provided. Read More

PLoS One 2021 19;16(2):e0247234. Epub 2021 Feb 19.

Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, United Kingdom.

Elevated reactive oxygen species (ROS) in type 2 diabetes cause cellular damage in many organs. Recently, the new class of glucose-lowering agents, SGLT-2 inhibitors, have been shown to reduce the risk of developing diabetic complications; however, the mechanisms of such beneficial effect are largely unknown. Here we aimed to investigate the effects of dapagliflozin on cell proliferation and cell death under oxidative stress conditions and explore its underlying mechanisms. Read More

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 Aug;49(4):439-446

Department of Hypertension, the First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China.

Objective: To investigate the expression of transient receptor potential canonical channels (TRPCs) in the heart and kidney of rat model of obstructive sleep apnea hypopnea syndrome (OSAHS).

Methods: Eighteen male SD rats were randomly assigned to intermittent hypoxia (IH) group (=9 ) and control group (=9). In IH group, rats were placed in a chamber and exposed to intermittent hypoxia for 8h (10AM-6PM) daily. Read More

Cells 2020 08 28;9(9). Epub 2020 Aug 28.

The Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Twenty-five years ago, the first mammalian Transient Receptor Potential Canonical (TRPC) channel was cloned, opening the vast horizon of the TRPC field. Today, we know that there are seven TRPC channels (TRPC1-7). TRPCs exhibit the highest protein sequence similarity to the TRP channels. Read More

Ann Palliat Med 2020 May 12;9(3):895-902. Epub 2020 May 12.

Department of Hypertension, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China.

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. Read More

J Neurogastroenterol Motil 2020 09;26(4):521-528

Department of Physiology, College of Medicine, Chosun University, Gwangju, Korea.

Background/aims: To investigate an effect of ML204 (an inhibitor of transient receptor potential canonical 4 and 5 [TRPC4/5] channels) on interstitial cells of Cajal (ICCs) and therefore determine whether TRPC4/5 channels act on ICC-generated pacemaker activity.

Methods: We enforced whole cell patch clamp analysis, measurements of the intracellular Ca concentration, and reverse transcription polymerase chain reaction to determine the effect of ML204 (10 μM) or englerin A (a selective activator of TRPC4/5 channeles, 10 μM) and the existence of TRPC4/5 in mouse small intestinal ICC.

Results: Treatment of ICCs with ML204 or englerin A caused the membrane potentials to depolarize. Read More

Cells 2020 02 18;9(2). Epub 2020 Feb 18.

Pharmakologisches Institut, BPC-Marburg, Fachbereich Medizin, Philipps-Universität Marburg, Karl-von-Frisch-Straße 2, 35043 Marburg, Germany.

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 and mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Read More

Front Physiol 2019 21;10:1618. Epub 2020 Jan 21.

Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy.

Vasculogenesis, angiogenesis and arteriogenesis represent three crucial mechanisms involved in the formation and maintenance of the vascular network in embryonal and post-natal life. It has long been known that endothelial Ca signals are key players in vascular remodeling; indeed, multiple pro-angiogenic factors, including vascular endothelial growth factor, regulate endothelial cell fate through an increase in intracellular Ca concentration. Transient Receptor Potential (TRP) channel consist in a superfamily of non-selective cation channels that are widely expressed within vascular endothelial cells. Read More

Cells 2020 02 5;9(2). Epub 2020 Feb 5.

German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany.

Persistent neural activity has been observed in vivo during working memory tasks, and supports short-term (up to tens of seconds) retention of information. While synaptic and intrinsic cellular mechanisms of persistent firing have been proposed, underlying cellular mechanisms are not yet fully understood. In vitro experiments have shown that individual neurons in the hippocampus and other working memory related areas support persistent firing through intrinsic cellular mechanisms that involve the transient receptor potential canonical (TRPC) channels. Read More

Medicina (Kaunas) 2019 Jul 16;55(7). Epub 2019 Jul 16.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Odbojarov 10, 83232 Bratislava, Slovakia.

: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Read More

Br J Pharmacol 2019 10 6;176(20):3924-3938. Epub 2019 Sep 6.

Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.

Background And Purpose: The TRPC1, TRPC4, and TRPC5 proteins form homotetrameric or heterotetrameric, calcium-permeable cation channels that are involved in various disease states. Recent research has yielded specific and potent xanthine-based TRPC1/4/5 inhibitors. Here, we investigated the possibility of xanthine-based activators of these channels. Read More

Pflugers Arch 2019 08 20;471(8):1045-1053. Epub 2019 Jun 20.

Department of Physiology, College of Medicine, Seoul National University, Seoul, South Korea.

Transient receptor potential canonical (TRPC) channels are calcium permeable, non-selective cation channels with wide tissue-specific distribution. Among 7 TRPC channels, TRPC 1/4/5 and TRPC3/6/7 are subdivided based on amino acid sequence homology. TRPC4 and TRPC5 channels exhibit cationic current with homotetrameric form, but they also form heterotetrameric channel such as TRPC1/4 or TRPC1/5 once TRPC1 is incorporated. Read More

Life Sci 2019 Aug 13;231:116567. Epub 2019 Jun 13.

Department of Oral Physiology, School of Dentistry, Kyungpook National University, 2177, Dalgubeol-daero, Jung-gu, Daegu, 41940, Republic of Korea.

Aims: Metabotropic glutamate receptor 5 (mGluR5), a member of group I mGluR, exerts its effect via elevation of intracellular Ca level. We here characterized Ca signals in the tsA201 cells transfected with mGluR5 and investigated the role of passages for mGluR5-induced Ca signals in synaptic plasticity.

Main Methods: Using a genetically encoded Ca indicator, GCamp2, Ca signals were reliably induced by bath application of (S)-3,5-dihydroxyphenylglycine, the group I mGluR agonist, in the tsA201 cells transfected with mGluR5. Read More

Avian Pathol 2019 Oct 19;48(5):429-436. Epub 2019 Jul 19.

College of Veterinary Medicine, South China Agricultural University , Guangzhou , P. R. People's Republic of China.

Ascites syndrome (AS) in chickens is associated with profound vascular remodelling and increased pulmonary artery pressure as well as right ventricular hypertrophy. Classical transient receptor potential cation channels (TRPCs) are key regulators of cardiac hypertrophy that act regulation of calcium influx in mammals. We investigated whether classical transient receptor potential channels in chickens with right ventricular hypertrophy still possess this mechanism for regulating Ca flux. Read More

J Cell Sci 2019 05 31;132(11). Epub 2019 May 31.

Department of Cell and Systems Physiology University of Occupational and Environmental Health School of Medicine, Kitakyushu 807-8555, Japan

Muscarinic receptor stimulation results in activation of nonselective cation (NSC) channels in guinea pig adrenal medullary (AM) cells. The biophysical and pharmacological properties of the NSC channel suggest the involvement of heteromeric channels of TRPC1 with TRPC4 or TRPC5. This possibility was explored in PC12 cells and guinea pig AM cells. Read More

Hippocampus 2019 11 19;29(11):1038-1048. Epub 2019 Apr 19.

Institute of Physiology and Pathophysiology, Heidelberg University, Heidelberg, Germany.

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. Read More

Cell Calcium 2019 06 14;80:25-28. Epub 2019 Mar 14.

Howard Hughes Medical Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA. Electronic address:

Briefly review the recent structural work of transient receptor potential canonical (TRPC) ion channels by using electron cryo-microscopy (cryo-EM). The high resolution structures of TRPC3, TRPC4, TRPC5 and TRPC6 are discussed. Read More

Sci Rep 2019 02 12;9(1):1849. Epub 2019 Feb 12.

Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

Transient receptor potential canonical (TRPC) 4 and TRPC5 channels are modulated by the Gα-PLC pathway. Since phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) maintains TRPC4 and TRPC5 channel function, the Gα-PLC pathway inhibits channel activity by depleting PI(4,5)P. Here we investigated the difference in PI(4,5)P sensitivity between homomeric and heteromeric TRPC channels. Read More

Br J Pharmacol 2019 04 6;176(7):832-846. Epub 2019 Mar 6.

Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, University of Hull, Hull, UK.

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. Read More

Cells 2018 Nov 20;7(11). Epub 2018 Nov 20.

Walther Straub Institute of Pharmacology and Toxicology, Ludwig Maximilians University of Munich, 80336 Munich, Germany.

Transient receptor potential classical or canonical 4 (TRPC4) and TRPC5 channels are members of the classical or canonical transient receptor potential (TRPC) channel family of non-selective cation channels. TRPC4 and TRPC5 channels are widely accepted as receptor-operated cation channels that are activated in a phospholipase C-dependent manner, following the G protein-coupled receptor activation. However, their precise activation mechanism has remained largely elusive for a long time, as the TRPC4 and TRPC5 channels were considered as being insensitive to the second messenger diacylglycerol (DAG) in contrast to the other TRPC channels. Read More

Front Cell Neurosci 2018 14;12:318. Epub 2018 Sep 14.

Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.

Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms. Read More

Sci Rep 2018 08 14;8(1):12117. Epub 2018 Aug 14.

Department of Physiology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.

The transient receptor potential canonical (TRPC) 1 channel is widely distributed in mammalian cells and is involved in many physiological processes. TRPC1 is primarily considered a regulatory subunit that forms heterotetrameric channels with either TRPC4 or TRPC5 subunits. Here, we suggest that the regulation of TRPC1/4 and TRPC1/5 heterotetrameric channels by the Gα-PLCβ pathway is self-limited and dynamically mediated by Gα and PI(4,5)P. Read More

Oncotarget 2018 Jul 3;9(51):29634-29643. Epub 2018 Jul 3.

School of Medicine, University of Leeds, Leeds, LS2 9JT, England, UK.

(-)-Englerin A (EA) is a natural product which has potent cytotoxic effects on renal cell carcinoma cells and other types of cancer cell but not non-cancer cells. Although selectively cytotoxic to cancer cells, adverse reaction in mice and rats has been suggested. EA is a remarkably potent activator of ion channels formed by Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) and TRPC4 is essential for EA-mediated cancer cell cytotoxicity. Read More

Oxid Med Cell Longev 2018 10;2018:4904696. Epub 2018 Jun 10.

Programa de Pós-graduação, Universidade Ceuma, Rua dos Castanheiros, no 1, Renascença II, São Luís, MA, Brazil.

Thioredoxin plays an essential role in bacterial antioxidant machinery and virulence; however, its regulatory actions in the host are less well understood. Reduced human Trx activates transient receptor potential canonical 5 (TRPC5) in inflammation, but there is no evidence of whether these receptors mediate bacterial thioredoxin effects in the host. Importantly, TRPC5 can form functional complexes with other subunits such as TRPC4. Read More

Sci Rep 2018 06 18;8(1):9264. Epub 2018 Jun 18.

Smooth Muscle Research Centre, Dundalk Institute of Technology, Dublin Road, Dundalk, Co. Louth, Ireland.

Acetylcholine contracts the bladder by binding to muscarinic M3 receptors on the detrusor, leading to Ca influx via voltage-gated Ca channels. The cellular mechanisms linking these events are poorly understood, but studies have suggested that activation of TRPC4 channels could be involved. The purpose of this study was to investigate if spontaneous and cholinergic-mediated contractions of the detrusor were impaired in TRPC4 deficient (TRPC4) mice. Read More

Cells 2018 Jun 1;7(6). Epub 2018 Jun 1.

Department of Discovery and Translational Science, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds LS2 9JT, UK.

Proteins of the TRPC family can form many homo- and heterotetrameric cation channels permeable to Na⁺, K⁺ and Ca. In this review, we focus on channels formed by the isoforms TRPC1, TRPC4 and TRPC5. We review evidence for the formation of different TRPC1/4/5 tetramers, give an overview of recently developed small-molecule TRPC1/4/5 activators and inhibitors, highlight examples of biological roles of TRPC1/4/5 channels in different tissues and pathologies, and discuss how high-quality chemical probes of TRPC1/4/5 modulators can be used to understand the involvement of TRPC1/4/5 channels in physiological and pathophysiological processes. Read More

Br J Pharmacol 2018 08 28;175(16):3361-3368. Epub 2018 Jun 28.

School of Medicine, University of Leeds, Leeds, UK.

Background And Purpose: The diterpene ester tonantzitlolone (TZL) is a natural product, which displays cytotoxicity towards certain types of cancer cell such as renal cell carcinoma cells. The effect is similar to that of (-)-englerin A, and so, although it is chemically distinct, we investigated whether TZL also targets transient receptor potential canonical (TRPC) channels of the 1, 4 and 5 type (TRPC1/4/5 channels).

Experimental Approach: The effects of TZL on renal cell carcinoma A498 cells natively expressing TRPC1 and TRPC4, modified HEK293 cells overexpressing TRPC4, TRPC5, TRPC4-TRPC1 or TRPC5-TRPC1 concatemer, TRPC3 or TRPM2, or CHO cells overexpressing TRPV4 were studied by determining changes in intracellular Ca , or whole-cell or excised membrane patch-clamp electrophysiology. Read More

PLoS One 2018 31;13(1):e0191225. Epub 2018 Jan 31.

Hydra Biosciences, Cambridge, Massachusetts, United States of America.

Background: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. Read More

Br J Pharmacol 2018 03 25;175(5):830-839. Epub 2018 Jan 25.

School of Medicine, University of Leeds, Leeds, UK.

Background And Purpose: (-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Read More