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Alexander Dietrich - One of the best experts on this subject based on the ideXlab platform.
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murine cardiac growth trpc channels and cgmp kinase i
Pflügers Archiv: European Journal of Physiology, 2015Co-Authors: Katrin Domes, Lutz Birnbaumer, Alexander Dietrich, Florian Loga, Jorg W Wegener, Enrico Patrucco, Franz HofmannAbstract:Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), TRPC6−/−, trpc3−/−, trpc3−/−/6−/−, βRM mice, and trpc3−/−/6−/− × βRM mice. βRM mice express cGKIβ only in the smooth muscle on a cGKI−/− background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, TRPC6−/−, trpc3−/−, trpc3−/−/6−/−, βRM, and trpc3−/−/6−/− × βRM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3 −/− mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and TRPC6−/−, minimal or absent in trpc3−/−, moderate in βRM, and dramatic in trpc3−/−/6−/− βRM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in βRM mice on a TRPC3/6 × cGKI−/−KO background, indicating an “additive” coupling between both signaling pathways.
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evidence for functional coupling of cgmp cgki signalling and trpc channels in endothelium but not in vascular smooth muscle
BMC Clinical Pharmacology, 2013Co-Authors: Florian Loga, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi, Alexander Dietrich, Katrin Domes, Franz Hofmann, Jorg W WegenerAbstract:Background Signaling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (TRPC) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on vascular tone and peripheral resistance using TRPC6, Trpc3, Trpc3/6, Trpc1/3/6, and SM-specific cGKI (sm-cGKI) mice.
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deletion of trpc4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo
Gastroenterology, 2009Co-Authors: Volodymyr Tsvilovskyy, Lutz Birnbaumer, Marc Freichel, Alexander Dietrich, Alexander Zholos, Thomas Aberle, Stephan E Philipp, Veit FlockerziAbstract:Background & Aims Downstream effects of muscarinic receptor stimulation in intestinal smooth muscle include contraction and intestinal transit. We thought to determine whether classic transient receptor potential (TRPC) channels integrate the intracellular signaling cascades evoked by the stimulated receptors and thereby contribute to the control of the membrane potential, Ca-influx, and cell responses. Methods We created trpc4 -, TRPC6 -, and trpc4/TRPC6 -gene–deficient mice and analyzed them for intestinal smooth muscle function in vitro and in vivo. Results In intestinal smooth muscle cells TRPC4 forms a 55 pS cation channel and underlies more than 80% of the muscarinic receptor-induced cation current (mI CAT ). The residual mI CAT depends on the expression of TRPC6, indicating that TRPC6 and TRPC4 determine mI CAT channel activity independent of other channel subunits. In TRPC4-deficient ileal myocytes the carbachol-induced membrane depolarizations are diminished greatly and the atropine-sensitive contraction elicited by acetylcholine release from excitatory motor neurons is reduced greatly. Additional deletion of TRPC6 aggravates these effects. Intestinal transit is slowed down in mice lacking TRPC4 and TRPC6. Conclusions In intestinal smooth muscle cells TRPC4 and TRPC6 channels are gated by muscarinic receptors and are responsible for mI CAT . They couple muscarinic receptors to depolarization of intestinal smooth muscle cells and voltage-activated Ca 2+ -influx and contraction, and thereby accelerate small intestinal motility in vivo.
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in vivo trpc functions in the cardiopulmonary vasculature
Cell Calcium, 2007Co-Authors: Alexander Dietrich, Hermann Kalwa, Beate Fuchs, Friedrich Grimminger, Norbert Weissmann, Thomas GudermannAbstract:Cardiovascular diseases are the leading cause of death in the industrialized countries. The cardiovascular system includes the systemic blood circulation, the heart and the pulmonary circulation providing sufficient blood flow and oxygen to peripheral tissues and organs according to their metabolic demand. This review focuses on three major cell types of the cardiovascular system: myocytes of the heart as well as smooth muscle cells and endothelial cells from the systemic and pulmonary circulation. Ion channels initiate and regulate contraction in all three cell types, and the identification of their genes has significantly improved our knowledge of signal transduction pathways in these cells. Among the ion channels expressed in smooth muscle cells, cation channels of the TRPC family allow for the entry of Na + and Ca 2+ . Physiological functions of TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 in the cardiovascular system, dissected by downregulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models, are reviewed. Possible functional roles and physiological regulation of TRPCs as homomeric or heteromeric channels in these cell types are discussed. Moreover, TRP channels may also be responsible for pathophysiological processes of the cardiovascular system like hypertension as well as cardiac hypertrophy and increased endothelial permeability. © 2007 Elsevier Ltd. All rights reserved.
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Increased vascular smooth muscle contractility in TRPC6-/- mice.
Molecular and cellular biology, 2005Co-Authors: Alexander Dietrich, Eda Yildirim, Michael Mederos Y Schnitzler, Maik Gollasch, Volkmar Gross, Ursula Storch, Galyna Dubrovska, Michael Obst, Birgit Salanova, Hermann KalwaAbstract:Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TRPC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TRPC6(-)(/)(-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.
Veit Flockerzi - One of the best experts on this subject based on the ideXlab platform.
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evidence for functional coupling of cgmp cgki signalling and trpc channels in endothelium but not in vascular smooth muscle
BMC Clinical Pharmacology, 2013Co-Authors: Florian Loga, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi, Alexander Dietrich, Katrin Domes, Franz Hofmann, Jorg W WegenerAbstract:Background Signaling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (TRPC) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on vascular tone and peripheral resistance using TRPC6, Trpc3, Trpc3/6, Trpc1/3/6, and SM-specific cGKI (sm-cGKI) mice.
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deletion of trpc4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo
Gastroenterology, 2009Co-Authors: Volodymyr Tsvilovskyy, Lutz Birnbaumer, Marc Freichel, Alexander Dietrich, Alexander Zholos, Thomas Aberle, Stephan E Philipp, Veit FlockerziAbstract:Background & Aims Downstream effects of muscarinic receptor stimulation in intestinal smooth muscle include contraction and intestinal transit. We thought to determine whether classic transient receptor potential (TRPC) channels integrate the intracellular signaling cascades evoked by the stimulated receptors and thereby contribute to the control of the membrane potential, Ca-influx, and cell responses. Methods We created trpc4 -, TRPC6 -, and trpc4/TRPC6 -gene–deficient mice and analyzed them for intestinal smooth muscle function in vitro and in vivo. Results In intestinal smooth muscle cells TRPC4 forms a 55 pS cation channel and underlies more than 80% of the muscarinic receptor-induced cation current (mI CAT ). The residual mI CAT depends on the expression of TRPC6, indicating that TRPC6 and TRPC4 determine mI CAT channel activity independent of other channel subunits. In TRPC4-deficient ileal myocytes the carbachol-induced membrane depolarizations are diminished greatly and the atropine-sensitive contraction elicited by acetylcholine release from excitatory motor neurons is reduced greatly. Additional deletion of TRPC6 aggravates these effects. Intestinal transit is slowed down in mice lacking TRPC4 and TRPC6. Conclusions In intestinal smooth muscle cells TRPC4 and TRPC6 channels are gated by muscarinic receptors and are responsible for mI CAT . They couple muscarinic receptors to depolarization of intestinal smooth muscle cells and voltage-activated Ca 2+ -influx and contraction, and thereby accelerate small intestinal motility in vivo.
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functional role of trpc proteins in native systems implications from knockout and knock down studies
The Journal of Physiology, 2005Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Stephan Philipp, Petra Weisgerber, Veit FlockerziAbstract:Available data on transient receptor potential channel (TRPC) protein functions indicate that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent cation entry pathways in primary cells which contribute to the elevation of cytosolic Ca2+. In addition, a striking number of biological functions have already been assigned to the various TRPC proteins, including mechanosensing activity (TRPC1), chemotropic axon guidance (TRPC1 and TRPC3), pheromone sensing and the regulation of sexual and social behaviour (TRPC2), endothelial-dependent regulation of vascular tone, endothelial permeability and neurotransmitter release (TRPC4), axonal growth (TRPC5), modulation of smooth muscle tone in blood vessels and lung and regulation of podocyte structure and function in the kidney (TRPC6). The lack of compounds which specifically block or activate TRPC proteins impairs the analysis of TRPC function in primary cells. We therefore concentrate in this contribution on (i) studies of TRPC-deficient mouse lines, (ii) data obtained by gene-silencing approaches using antisense oligonucleotides or RNA interference, (iii) expression experiments employing dominant negative TRPC constructs, and (iv) recent data correlating mutations of TRPC genes associated with human disease.
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Functional role of TRPC proteins in native systems: implications from knockout and knock‐down studies
The Journal of Physiology, 2005Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Stephan Philipp, Petra Weißgerber, Veit FlockerziAbstract:Available data on transient receptor potential channel (TRPC) protein functions indicate that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent cation entry pathways in primary cells which contribute to the elevation of cytosolic Ca2+. In addition, a striking number of biological functions have already been assigned to the various TRPC proteins, including mechanosensing activity (TRPC1), chemotropic axon guidance (TRPC1 and TRPC3), pheromone sensing and the regulation of sexual and social behaviour (TRPC2), endothelial-dependent regulation of vascular tone, endothelial permeability and neurotransmitter release (TRPC4), axonal growth (TRPC5), modulation of smooth muscle tone in blood vessels and lung and regulation of podocyte structure and function in the kidney (TRPC6). The lack of compounds which specifically block or activate TRPC proteins impairs the analysis of TRPC function in primary cells. We therefore concentrate in this contribution on (i) studies of TRPC-deficient mouse lines, (ii) data obtained by gene-silencing approaches using antisense oligonucleotides or RNA interference, (iii) expression experiments employing dominant negative TRPC constructs, and (iv) recent data correlating mutations of TRPC genes associated with human disease.
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Functional role of TRPC proteins in vivo: lessons from TRPC-deficient mouse models.
Biochemical and biophysical research communications, 2004Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Petra Weißgerber, M. Hoffmann, C. Müller, J. Scheunemann, Veit FlockerziAbstract:In order to elucidate the functional role of TRPC genes, in vivo, the targeted inactivation of these genes in mice is an invaluable technique. In this review, we summarize the currently available results on the phenotype of TRPC-deficient mouse lines. The analysis of mice with targeted deletion in three TRPC genes demonstrates that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent Ca2+ entry channels in primary cells. Furthermore, from the deficits observed in these TRPC-deficient mouse lines a striking number of biological functions could already be ascribed to TRPC2, TRPC4, and TRPC6, not only on the cellular level but also for complex organ functions and integrative physiology. Accordingly, TRPC2 proteins are critically involved in pheromone sensing by neurones of the vomeronasal organ and, thereby, in the regulation of sexual and social behavior of mice, TRPC4 proteins are essential determinants of endothelial-dependent regulation of vascular tone, endothelial permeability, and neurotransmitter release from thalamic interneurones, and TRPC6 proteins are supposed to have a fundamental role in the regulation of smooth muscle tone in blood vessels and lung.
Hermann Kalwa - One of the best experts on this subject based on the ideXlab platform.
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in vivo trpc functions in the cardiopulmonary vasculature
Cell Calcium, 2007Co-Authors: Alexander Dietrich, Hermann Kalwa, Beate Fuchs, Friedrich Grimminger, Norbert Weissmann, Thomas GudermannAbstract:Cardiovascular diseases are the leading cause of death in the industrialized countries. The cardiovascular system includes the systemic blood circulation, the heart and the pulmonary circulation providing sufficient blood flow and oxygen to peripheral tissues and organs according to their metabolic demand. This review focuses on three major cell types of the cardiovascular system: myocytes of the heart as well as smooth muscle cells and endothelial cells from the systemic and pulmonary circulation. Ion channels initiate and regulate contraction in all three cell types, and the identification of their genes has significantly improved our knowledge of signal transduction pathways in these cells. Among the ion channels expressed in smooth muscle cells, cation channels of the TRPC family allow for the entry of Na + and Ca 2+ . Physiological functions of TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 in the cardiovascular system, dissected by downregulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models, are reviewed. Possible functional roles and physiological regulation of TRPCs as homomeric or heteromeric channels in these cell types are discussed. Moreover, TRP channels may also be responsible for pathophysiological processes of the cardiovascular system like hypertension as well as cardiac hypertrophy and increased endothelial permeability. © 2007 Elsevier Ltd. All rights reserved.
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Increased vascular smooth muscle contractility in TRPC6-/- mice.
Molecular and cellular biology, 2005Co-Authors: Alexander Dietrich, Eda Yildirim, Michael Mederos Y Schnitzler, Maik Gollasch, Volkmar Gross, Ursula Storch, Galyna Dubrovska, Michael Obst, Birgit Salanova, Hermann KalwaAbstract:Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TRPC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TRPC6(-)(/)(-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.
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increased vascular smooth muscle contractility in TRPC6 mice
Molecular and Cellular Biology, 2005Co-Authors: Alexander Dietrich, Eda Yildirim, Maik Gollasch, Volkmar Gross, Ursula Storch, Galyna Dubrovska, Michael Obst, Birgit Salanova, Michael Mederos Y Schnitzler, Hermann KalwaAbstract:Among the TRPC subfamily of TRP (classical transient receptor potential) channels, TRPC3, -6, and -7 are gated by signal transduction pathways that activate C-type phospholipases as well as by direct exposure to diacylglycerols. Since TRPC6 is highly expressed in pulmonary and vascular smooth muscle cells, it represents a likely molecular candidate for receptor-operated cation entry. To define the physiological role of TRPC6, we have developed a TRPC6-deficient mouse model. These mice showed an elevated blood pressure and enhanced agonist-induced contractility of isolated aortic rings as well as cerebral arteries. Smooth muscle cells of TRPC6-deficient mice have higher basal cation entry, increased TRPC-carried cation currents, and more depolarized membrane potentials. This higher basal cation entry, however, was completely abolished by the expression of a TRPC3-specific small interference RNA in primary TRPC6(-)(/)(-) smooth muscle cells. Along these lines, the expression of TRPC3 in wild-type cells resulted in increased basal activity, while TRPC6 expression in TRPC6(-/-) smooth muscle cells reduced basal cation influx. These findings imply that constitutively active TRPC3-type channels, which are up-regulated in TRPC6-deficient smooth muscle cells, are not able to functionally replace TRPC6. Thus, TRPC6 has distinct nonredundant roles in the control of vascular smooth muscle tone.
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n linked protein glycosylation is a major determinant for basal trpc3 and TRPC6 channel activity
Journal of Biological Chemistry, 2003Co-Authors: Alexander Dietrich, Hermann Kalwa, Michael Mederos Y Schnitzler, Jens Emmel, Thomas Hofmann, Thomas GudermannAbstract:Abstract The TRPC family of receptor-activated cation channels (TRPC channels) can be subdivided into four subfamilies based on sequence homology as well as functional similarities. Members of the TRPC3/6/7 subfamily share common biophysical characteristics and are activated by diacylglycerol in a membrane-delimited manner. At present, it is only poorly understood whether members of the TRPC3/6/7 subfamily are functionally redundant or whether they serve distinct cellular roles. By electrophysiological and fluorescence imaging strategies we show that TRPC3 displays considerable constitutive activity, while TRPC6 is a tightly regulated channel. To identify potential molecular correlates accounting for the functional difference, we analyzed the glycosylation pattern of TRPC6 compared with TRPC3. Two NX(S/T) motifs in TRPC6 were mutated (Asn to Gln) by in vitro mutagenesis to delete one or both extracellular N-linked glycosylation sites. Immunoblotting analysis of HEK 293 cell lysates expressing TRPC6 wild type and mutants favors a model of TRPC6 that is dually glycosylated within the first (e1) and second extracelluar loop (e2) as opposed to the monoglycosylated TRPC3 channel (Vannier, B., Zhu, X., Brown, D., and Birnbaumer, L. (1998) J. Biol. Chem. 273, 8675–8679). Elimination of the e2 glycosylation site, missing in the monoglycosylated TRPC3, was sufficient to convert the tightly receptor-regulated TRPC6 into a constitutively active channel, displaying functional characteristics of TRPC3. Reciprocally, engineering of an additional second glycosylated site in TRPC3 to mimic the glycosylation status in TRPC6 markedly reduced TRPC3 basal activity. We conclude that the glycosylation pattern plays a pivotal role for the tight regulation of TRPC6 through phospholipase C-activating receptors.
Lutz Birnbaumer - One of the best experts on this subject based on the ideXlab platform.
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trpc1 and trpc3 dependent ca2 signaling in mouse cortical astrocytes affects injury evoked astrogliosis in vivo
Glia, 2017Co-Authors: Thabet Belkacemi, Lutz Birnbaumer, Alexander Niermann, Laura Hofmann, Ulrich Wissenbach, Petra Leidinger, Christina Backes, Eckart Meese, Andreas KellerAbstract:Following brain injury astrocytes change into a reactive state, proliferate and grow into the site of lesion, a process called astrogliosis, initiated and regulated by changes in cytoplasmic Ca2+ . Transient receptor potential canonical (TRPC) channels may contribute to Ca2+ influx but their presence and possible function in astrocytes is not known. By RT-PCR and RNA sequencing we identified transcripts of Trpc1, Trpc2, Trpc3, and Trpc4 in FACS-sorted glutamate aspartate transporter (GLAST)-positive cultured mouse cortical astrocytes and subcloned full-length Trpc1 and Trpc3 cDNAs from these cells. Ca2+ entry in cortical astrocytes depended on TRPC3 and was increased in the absence of Trpc1. After co-expression of Trpc1 and Trpc3 in HEK-293 cells both proteins co-immunoprecipitate and form functional heteromeric channels, with TRPC1 reducing TRPC3 activity. In vitro, lack of Trpc3 reduced astrocyte proliferation and migration whereas the TRPC3 gain-of-function moonwalker mutation and Trpc1 deficiency increased astrocyte migration. In vivo, astrogliosis and cortex edema following stab wound injury were reduced in Trpc3-/- but increased in Trpc1-/- mice. In summary, our results show a decisive contribution of TRPC3 to astrocyte Ca2+ signaling, which is even augmented in the absence of Trpc1, in particular following brain injury. Targeted therapies to reduce TRPC3 channel activity in astrocytes might therefore be beneficial in traumatic brain injury.
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deletion of diacylglycerol responsive trpc genes attenuates diabetic nephropathy by inhibiting activation of the tgfβ1 signaling pathway
American Journal of Translational Research, 2017Co-Authors: Benju Liu, Lutz Birnbaumer, Yanhong LiaoAbstract:TRPC6 plays a critical role in proteinuric kidney diseases, and TRPC3 is involved in tubulointerstitial damage and renal fibrosis in obstructed kidneys. Podocyte loss is a characteristic event in diabetic nephropathy (DN). The aim of this study was to examine whether deletion of the closely related diacylglycerol (DAG)-responsive TRPCs in mice (TRPC3/6/7-/-) affects diabetes-induced renal dysfunction and podocyte loss. We compared urine volume, kidney hypertrophy, glomerular enlargement, albuminuria and podocyte loss between wild type (WT) and TRPC3/6/7-/- diabetic mice. Finally, we examined whether the TGFβ1 signaling pathway is changed in diabetic WT and TRPC3/6/7-/- mice. TRPC6 protein in the renal cortex was increased in WT diabetic mice. High glucose (HG) treatment increased TRPC6 expression in human podocytes. TRPC3 protein, however, was not altered in either diabetic mice or HG-treated human podocytes. Although diabetic WT and TRPC3/6/7-/- mice had similar levels of hyperglycemia, the TRPC3/6/7-/- diabetic mice showed less polyuria, kidney hypertrophy, glomerular enlargement, albuminuria, and had lost less podocytes compared with WT diabetic mice. In addition, we observed decreased expression of anti-apoptotic Bcl2 and increased expression of pro-apoptotic cleaved caspase 3 in WT diabetic mice, but such changes were not significant in TRPC3/6/7-/- diabetic mice. Western blot and immunohistochemistry revealed that TGFβ1, p-Smad2/3, and fibronectin were upregulated in WT diabetic mice; however, expression of these signaling molecules was not changed in TRPC3/6/7-/- diabetic mice. In conclusion, deletion of DAG-responsive TRPCs attenuates diabetic renal injury via inhibiting the upregulation of TGFβ1 signaling in diabetic kidneys.
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the contribution of trpc1 trpc3 trpc5 and TRPC6 to touch and hearing
Neuroscience Letters, 2016Co-Authors: Jane E Sexton, Joel Abramowitz, Lutz Birnbaumer, Terri Desmonds, Kathryn Quick, Ruth Taylor, Andy Forge, Corne J Kros, John WoodAbstract:Transient receptor potential channels have diverse roles in mechanosensation. Evidence is accumulating that members of the canonical subfamily of TRP channels (TRPC) are involved in touch and hearing. Characteristic features of TRP channels include their high structural homology and their propensity to form heteromeric complexes which suggests potential functional redundancy. We previously showed that TRPC3 and TRPC6 double knockout animals have deficits in light touch and hearing whilst single knockouts were apparently normal. We have extended these studies to analyse deficits in global quadruple TRPC1, 3, 5 and 6 null mutant mice. We examined both touch and hearing in behavioural and electrophysiological assays, and provide evidence that the quadruple knockout mice have larger deficits than the TRPC3 TRPC6 double knockouts. Mechano-electrical transducer currents of cochlear outer hair cells were however normal. This suggests that TRPC1, TRPC3, TRPC5 and TRPC6 channels contribute to cutaneous and auditory mechanosensation in a combinatorial manner, but have no direct role in cochlear mechanotransduction.
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murine cardiac growth trpc channels and cgmp kinase i
Pflügers Archiv: European Journal of Physiology, 2015Co-Authors: Katrin Domes, Lutz Birnbaumer, Alexander Dietrich, Florian Loga, Jorg W Wegener, Enrico Patrucco, Franz HofmannAbstract:Signaling via cGMP-dependent protein kinase I (cGKI) and canonical transient receptor potential (TRPC) channels appears to be involved in the regulation of cardiac hypertrophy. Recent evidence suggests that TRPC channels are targets for cGKI, and phosphorylation of these channels may mediate the antihypertrophic effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on angiotensin II (A II)-induced cardiac hypertrophy using a control group (Ctr), TRPC6−/−, trpc3−/−, trpc3−/−/6−/−, βRM mice, and trpc3−/−/6−/− × βRM mice. βRM mice express cGKIβ only in the smooth muscle on a cGKI−/− background. The control group was composed of littermate mice that contained at least one wild type gene of the respective genotype. A II was infused by minipumps (7 days; 2 mg/kg/day) in Ctr, TRPC6−/−, trpc3−/−, trpc3−/−/6−/−, βRM, and trpc3−/−/6−/− × βRM mice. Hypertrophy was assessed by measuring heart weight per tibia length (HW/TL) and fibrosis by staining of heart slices. A II-induced increase in HW/TL and fibrosis was absent in trpc3 −/− mice, whereas an increase in HW/TL and fibrosis was evident in Ctr and TRPC6−/−, minimal or absent in trpc3−/−, moderate in βRM, and dramatic in trpc3−/−/6−/− βRM mice. These results suggest that TRPC3 may be necessary for A II-induced cardiac hypertrophy. On the other hand, hypertrophy and fibrosis were massively increased in βRM mice on a TRPC3/6 × cGKI−/−KO background, indicating an “additive” coupling between both signaling pathways.
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evidence for functional coupling of cgmp cgki signalling and trpc channels in endothelium but not in vascular smooth muscle
BMC Clinical Pharmacology, 2013Co-Authors: Florian Loga, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi, Alexander Dietrich, Katrin Domes, Franz Hofmann, Jorg W WegenerAbstract:Background Signaling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (TRPC) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on vascular tone and peripheral resistance using TRPC6, Trpc3, Trpc3/6, Trpc1/3/6, and SM-specific cGKI (sm-cGKI) mice.
Marc Freichel - One of the best experts on this subject based on the ideXlab platform.
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evidence for functional coupling of cgmp cgki signalling and trpc channels in endothelium but not in vascular smooth muscle
BMC Clinical Pharmacology, 2013Co-Authors: Florian Loga, Lutz Birnbaumer, Marc Freichel, Veit Flockerzi, Alexander Dietrich, Katrin Domes, Franz Hofmann, Jorg W WegenerAbstract:Background Signaling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (TRPC) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on vascular tone and peripheral resistance using TRPC6, Trpc3, Trpc3/6, Trpc1/3/6, and SM-specific cGKI (sm-cGKI) mice.
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deletion of trpc4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo
Gastroenterology, 2009Co-Authors: Volodymyr Tsvilovskyy, Lutz Birnbaumer, Marc Freichel, Alexander Dietrich, Alexander Zholos, Thomas Aberle, Stephan E Philipp, Veit FlockerziAbstract:Background & Aims Downstream effects of muscarinic receptor stimulation in intestinal smooth muscle include contraction and intestinal transit. We thought to determine whether classic transient receptor potential (TRPC) channels integrate the intracellular signaling cascades evoked by the stimulated receptors and thereby contribute to the control of the membrane potential, Ca-influx, and cell responses. Methods We created trpc4 -, TRPC6 -, and trpc4/TRPC6 -gene–deficient mice and analyzed them for intestinal smooth muscle function in vitro and in vivo. Results In intestinal smooth muscle cells TRPC4 forms a 55 pS cation channel and underlies more than 80% of the muscarinic receptor-induced cation current (mI CAT ). The residual mI CAT depends on the expression of TRPC6, indicating that TRPC6 and TRPC4 determine mI CAT channel activity independent of other channel subunits. In TRPC4-deficient ileal myocytes the carbachol-induced membrane depolarizations are diminished greatly and the atropine-sensitive contraction elicited by acetylcholine release from excitatory motor neurons is reduced greatly. Additional deletion of TRPC6 aggravates these effects. Intestinal transit is slowed down in mice lacking TRPC4 and TRPC6. Conclusions In intestinal smooth muscle cells TRPC4 and TRPC6 channels are gated by muscarinic receptors and are responsible for mI CAT . They couple muscarinic receptors to depolarization of intestinal smooth muscle cells and voltage-activated Ca 2+ -influx and contraction, and thereby accelerate small intestinal motility in vivo.
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functional role of trpc proteins in native systems implications from knockout and knock down studies
The Journal of Physiology, 2005Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Stephan Philipp, Petra Weisgerber, Veit FlockerziAbstract:Available data on transient receptor potential channel (TRPC) protein functions indicate that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent cation entry pathways in primary cells which contribute to the elevation of cytosolic Ca2+. In addition, a striking number of biological functions have already been assigned to the various TRPC proteins, including mechanosensing activity (TRPC1), chemotropic axon guidance (TRPC1 and TRPC3), pheromone sensing and the regulation of sexual and social behaviour (TRPC2), endothelial-dependent regulation of vascular tone, endothelial permeability and neurotransmitter release (TRPC4), axonal growth (TRPC5), modulation of smooth muscle tone in blood vessels and lung and regulation of podocyte structure and function in the kidney (TRPC6). The lack of compounds which specifically block or activate TRPC proteins impairs the analysis of TRPC function in primary cells. We therefore concentrate in this contribution on (i) studies of TRPC-deficient mouse lines, (ii) data obtained by gene-silencing approaches using antisense oligonucleotides or RNA interference, (iii) expression experiments employing dominant negative TRPC constructs, and (iv) recent data correlating mutations of TRPC genes associated with human disease.
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Functional role of TRPC proteins in native systems: implications from knockout and knock‐down studies
The Journal of Physiology, 2005Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Stephan Philipp, Petra Weißgerber, Veit FlockerziAbstract:Available data on transient receptor potential channel (TRPC) protein functions indicate that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent cation entry pathways in primary cells which contribute to the elevation of cytosolic Ca2+. In addition, a striking number of biological functions have already been assigned to the various TRPC proteins, including mechanosensing activity (TRPC1), chemotropic axon guidance (TRPC1 and TRPC3), pheromone sensing and the regulation of sexual and social behaviour (TRPC2), endothelial-dependent regulation of vascular tone, endothelial permeability and neurotransmitter release (TRPC4), axonal growth (TRPC5), modulation of smooth muscle tone in blood vessels and lung and regulation of podocyte structure and function in the kidney (TRPC6). The lack of compounds which specifically block or activate TRPC proteins impairs the analysis of TRPC function in primary cells. We therefore concentrate in this contribution on (i) studies of TRPC-deficient mouse lines, (ii) data obtained by gene-silencing approaches using antisense oligonucleotides or RNA interference, (iii) expression experiments employing dominant negative TRPC constructs, and (iv) recent data correlating mutations of TRPC genes associated with human disease.
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Functional role of TRPC proteins in vivo: lessons from TRPC-deficient mouse models.
Biochemical and biophysical research communications, 2004Co-Authors: Marc Freichel, Rudi Vennekens, Jenny Olausson, Susanne Stolz, Petra Weißgerber, M. Hoffmann, C. Müller, J. Scheunemann, Veit FlockerziAbstract:In order to elucidate the functional role of TRPC genes, in vivo, the targeted inactivation of these genes in mice is an invaluable technique. In this review, we summarize the currently available results on the phenotype of TRPC-deficient mouse lines. The analysis of mice with targeted deletion in three TRPC genes demonstrates that these proteins represent essential constituents of agonist-activated and phospholipase C-dependent Ca2+ entry channels in primary cells. Furthermore, from the deficits observed in these TRPC-deficient mouse lines a striking number of biological functions could already be ascribed to TRPC2, TRPC4, and TRPC6, not only on the cellular level but also for complex organ functions and integrative physiology. Accordingly, TRPC2 proteins are critically involved in pheromone sensing by neurones of the vomeronasal organ and, thereby, in the regulation of sexual and social behavior of mice, TRPC4 proteins are essential determinants of endothelial-dependent regulation of vascular tone, endothelial permeability, and neurotransmitter release from thalamic interneurones, and TRPC6 proteins are supposed to have a fundamental role in the regulation of smooth muscle tone in blood vessels and lung.