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Trpc3 purkinje

Jana Hartmann, Arthur Konnerth
The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of the seven members of the TRPC subfamily, combines functions of an unspecific ion channel and a signal transducer. In the mammalian brain, the expression of TRPC3 is highest in cerebellar Purkinje cells, the principal neurons, and the sole output of the cerebellar cortex. In this review, we summarize findings identifying TRPC3 channels as integral components of glutamatergic metabotropic synaptic transmission...
September 2015: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Anna Dulneva, Sheena Lee, Peter L Oliver, Katalin Di Gleria, Benedikt M Kessler, Kay E Davies, Esther B E Becker
The Moonwalker (Mwk) mouse is a model of dominantly inherited cerebellar ataxia caused by a gain-of-function mutation in the transient receptor potential (TRP) channel TRPC3. Here, we report impairments in dendritic growth and synapse formation early on during Purkinje cell development in the Mwk cerebellum that are accompanied by alterations in calcium signaling. To elucidate the molecular effector pathways that regulate Purkinje cell dendritic arborization downstream of mutant TRPC3, we employed transcriptomic analysis of developing Purkinje cells isolated by laser-capture microdissection...
July 15, 2015: Human Molecular Genetics
Haibo Zhou, Zhanmin Lin, Kai Voges, Chiheng Ju, Zhenyu Gao, Laurens W J Bosman, Tom J H Ruigrok, Freek E Hoebeek, Chris I De Zeeuw, Martijn Schonewille
Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules...
2014: ELife
Jana Hartmann, Rosa M Karl, Ryan P D Alexander, Helmuth Adelsberger, Monika S Brill, Charlotta Rühlmann, Anna Ansel, Kenji Sakimura, Yoshihiro Baba, Tomohiro Kurosaki, Thomas Misgeld, Arthur Konnerth
In central mammalian neurons, activation of metabotropic glutamate receptor type1 (mGluR1) evokes a complex synaptic response consisting of IP3 receptor-dependent Ca(2+) release from internal Ca(2+) stores and a slow depolarizing potential involving TRPC3 channels. It is largely unclear how mGluR1 is linked to its downstream effectors. Here, we explored the role of stromal interaction molecule 1 (STIM1) in regulating neuronal Ca(2+) signaling and mGluR1-dependent synaptic transmission. By analyzing mouse cerebellar Purkinje neurons, we demonstrate that STIM1 is an essential regulator of the Ca(2+) level in neuronal endoplasmic reticulum Ca(2+) stores...
May 7, 2014: Neuron
Esther B E Becker
The Moonwalker (Mwk) mouse is a recent model of dominantly inherited cerebellar ataxia. The motor phenotype of the Mwk mouse is due to a gain-of-function mutation in the gene encoding the cation-permeable transient receptor potential channel (TRPC3). This mutation converts a threonine into an alanine in the highly conserved cytoplasmic S4-S5 linker of the channel, affecting channel gating. TRPC3 is highly expressed in cerebellar Purkinje cells and type II unipolar brush cells that both degenerate in the Mwk mouse...
October 2014: Cerebellum
Gabriella Sekerková, Jin-Ah Kim, Maximiliano J Nigro, Esther B E Becker, Jana Hartmann, Lutz Birnbaumer, Enrico Mugnaini, Marco Martina
Transient receptor potential "canonical" cation channels (TRPC) are involved in many cellular activities, including neuronal synaptic transmission. These channels couple lipid metabolism, calcium homeostasis, and electrophysiological properties as they are calcium permeable and activated through the phospholipase C pathway and by diacylglycerol. The TRPC3 subunit is abundantly expressed in Purkinje cells (PCs), where it mediates slow metabotropic glutamate receptor-mediated synaptic responses. Recently, it has been shown that heterozygous moonwalker mice, which are a model of cerebellar ataxia, carry a dominant gain-of-function mutation (T635A) in the TRPC3 gene...
December 11, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sang Jeong Kim
Cerebellar long-term depression (LTD) is induced by repetitive pairing of both synaptic inputs provided by climbing fibers (CFs) and parallel fibers (PFs), especially when CF stimulation followed by burst of PFs. Metabotropic glutamate receptor type 1 (mGluR1)-dependent signaling in Purkinje cells is critically involved in the induction of cerebellar LTD. Signaling pathway of mGluR1 has two limbs: one is IP3 receptor-mediated Ca release from intracellular Ca store and the other is activation of transient receptor potential canonical (TRPC) channels...
June 2013: Cerebellum
Akihiko S Kato, Michael D Knierman, Edward R Siuda, John T R Isaac, Eric S Nisenbaum, David S Bredt
Cerebellar motor coordination and cerebellar Purkinje cell synaptic function require metabotropic glutamate receptor 1 (mGluR1, Grm1). We used an unbiased proteomic approach to identify protein partners for mGluR1 in cerebellum and discovered glutamate receptor δ2 (GluRδ2, Grid2, GluΔ2) and protein kinase Cγ (PKCγ) as major interactors. We also found canonical transient receptor potential 3 (TRPC3), which is also needed for mGluR1-dependent slow EPSCs and motor coordination and associates with mGluR1, GluRδ2, and PKCγ...
October 31, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Youngsoo Kim, Ann Chi Yan Wong, John M Power, Sherif F Tadros, Matthias Klugmann, Andrew J Moorhouse, Paul P Bertrand, Gary D Housley
Canonical transient receptor potential (TRPC3) nonselective cation channels are effectors of G-protein-coupled receptors (GPCRs), activated via phospholipase C-diacylglycerol signaling. In cerebellar Purkinje cells, TRPC3 channels cause the metabotropic glutamate receptor (mGluR)-mediated slow EPSC (sEPSC). TRPC3 channels also provide negative feedback regulation of cytosolic Ca(2+), mediated by a C terminus "calmodulin and inositol trisphosphate receptor binding" (CIRB) domain. Here we report the alternative splicing of the TRPC3 mRNA transcript (designated TRPC3c), resulting in omission of exon 9 (approximately half of the CIRB domain) in mice, rats, and guinea pigs...
August 15, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Charmaine Nelson, Maike D Glitsch
Canonical transient receptor potential (TRPC) channels are widely expressed in the brain and play several roles in development and normal neuronal function. In the cerebellum, Purkinje cell TRPC3 channels underlie the slow excitatory postsynaptic potential observed after parallel fiber stimulation. In these cells TRPC3 channel opening requires stimulation of metabotropic glutamate receptor 1, activation of which can also lead to the induction of long term depression (LTD), which underlies cerebellar motor learning...
February 24, 2012: Journal of Biological Chemistry
Olivia S Gugger, Jana Hartmann, Lutz Birnbaumer, Josef P Kapfhammer
The development of a neuronal dendritic tree is modulated both by signals from afferent fibers and by an intrinsic program. We have previously shown that chronic activation of either type 1 metabotropic glutamate receptors (mGluR1s) or protein kinase C (PKC) in organotypic cerebellar slice cultures of mice and rats severely inhibits the growth and development of the Purkinje cell dendritic tree. The signaling events linking receptor activation to the regulation of dendritic growth remain largely unknown. We have studied whether channels allowing the entry of Ca(2+) into Purkinje cells, in particular the type 3 transient receptor potential cation channels (TRPC3s), P/Q-type Ca(2+) channels, and T-type Ca(2+) channels, might be involved in signaling after mGluR1 or PKC stimulation...
January 2012: European Journal of Neuroscience
Anton N Shuvaev, Hajime Horiuchi, Takahiro Seki, Hanna Goenawan, Tomohiko Irie, Akira Iizuka, Norio Sakai, Hirokazu Hirai
Cerebellar Purkinje cells (PCs) express a large amount of the γ isoform of protein kinase C (PKCγ) and a modest level of PKCα. The PKCγ is involved in the pruning of climbing fiber (CF) synapses from developing PCs, and PKCα plays a critical role in long-term depression (LTD) at parallel fiber (PF)-PC synapses. Moreover, the PKC signaling in PCs negatively modulates the nonselective transient receptor potential cation channel type 3 (TRPC3), the opening of which elicits slow EPSCs at PF-PC synapses. Autosomal dominant spinocerebellar ataxia type 14 (SCA14) is caused by mutations in PKCγ...
October 5, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Kazuhiro Mitsumura, Nobutake Hosoi, Nobuhiko Furuya, Hirokazu Hirai
Staggerer mutant mice have functional loss of a transcription factor, retinoid-related orphan receptor α (RORα), which is abundantly expressed in Purkinje cells (PCs) of the cerebellum.Homozygous staggerer (sg/sg)mice show cerebellar hypoplasia and congenital ataxia. Sg/sg mice serve as an important extreme mouse model of the hereditary spinocerebellar ataxia type 1 (SCA1), since it has been shown that RORα dysfunction is strongly correlated with SCA1 pathogenesis. However, synaptic abnormalities, especially at parallel fibre (PF)-PC synapses, in SCA1-related sg/sg mice have not been examined in detail electrophysiologically...
July 1, 2011: Journal of Physiology
Jana Hartmann, Horst A Henning, Arthur Konnerth
Metabotropic glutamate receptors type 1 (mGluR1s) are required for a normal function of the mammalian brain. They are particularly important for synaptic signaling and plasticity in the cerebellum. Unlike ionotropic glutamate receptors that mediate rapid synaptic transmission, mGluR1s produce in cerebellar Purkinje cells a complex postsynaptic response consisting of two distinct signal components, namely a local dendritic calcium signal and a slow excitatory postsynaptic potential. The basic mechanisms underlying these synaptic responses were clarified in recent years...
April 2011: Cold Spring Harbor Perspectives in Biology
Mohamed Trebak
Transient receptor potential canonical 3 (TRPC3) proteins are nonselective cation channels activated downstream of phospholipase-C-coupled receptors. TRPC3 channels have emerged as major players in the function of the central nervous system. They have been described as important contributors to brain-derived neurotrophic factor mediated survival and growth-cone guidance of cerebellar granule neurons. TRPC3 were also identified as postsynaptic cation channels essential for metabotropic glutamate receptor1-dependent synaptic transmission in cerebellar Purkinje neurons...
February 2010: Pflügers Archiv: European Journal of Physiology
Maike D Glitsch
In the mammalian nervous system, stimulation of G-protein-coupled type I glutamate receptors triggers various forms of neuronal plasticity, including cerebellar long-term depression and hippocampal long-term potentiation. Activation of these receptors in the cerebellum also leads to a slow excitatory postsynaptic current mediated by nonselective TRPC3 cation channels. How TRPC3 channels are opened is unknown, although it is widely thought that channel gating requires phospholipase C activation. Using the patch-clamp technique and immunohistochemistry in rat cerebellar slices, we show that metabotropic glutamate receptors activate TRPC3 channels through the small GTP-binding protein Rho and subsequent phospholipase D stimulation...
January 2010: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Esther B E Becker, Peter L Oliver, Maike D Glitsch, Gareth T Banks, Francesca Achilli, Andrea Hardy, Patrick M Nolan, Elizabeth M C Fisher, Kay E Davies
The hereditary ataxias are a complex group of neurological disorders characterized by the degeneration of the cerebellum and its associated connections. The molecular mechanisms that trigger the loss of Purkinje cells in this group of diseases remain incompletely understood. Here, we report a previously undescribed dominant mouse model of cerebellar ataxia, moonwalker (Mwk), that displays motor and coordination defects and loss of cerebellar Purkinje cells. Mwk mice harbor a gain-of-function mutation (T635A) in the Trpc3 gene encoding the nonselective transient receptor potential cation channel, type C3 (TRPC3), resulting in altered TRPC3 channel gating...
April 21, 2009: Proceedings of the National Academy of Sciences of the United States of America
Jana Hartmann, Arthur Konnerth
The metabotropic glutamate receptors type 1 (mGluR1s) are required for a normal function of the mammalian cerebellum. These G-protein coupled receptors are abundantly expressed in the principle cerebellar cells, namely the Purkinje neurons. Under physiological conditions, mGluR1s are activated during repetitive activity of both afferent glutamatergic synaptic inputs provided by the climbing and parallel fibers, respectively. Unlike the common ionotropic glutamate receptors that underlie rapid synaptic excitation, mGluR1s produce a complex postsynaptic response consisting of a Ca(2+) release signal from intracellular stores and a slow excitatory postsynaptic potential...
October 28, 2008: Acta Physiologica
Jana Hartmann, Elena Dragicevic, Helmuth Adelsberger, Horst A Henning, Martin Sumser, Joel Abramowitz, Robert Blum, Alexander Dietrich, Marc Freichel, Veit Flockerzi, Lutz Birnbaumer, Arthur Konnerth
In the mammalian central nervous system, slow synaptic excitation involves the activation of metabotropic glutamate receptors (mGluRs). It has been proposed that C1-type transient receptor potential (TRPC1) channels underlie this synaptic excitation, but our analysis of TRPC1-deficient mice does not support this hypothesis. Here, we show unambiguously that it is TRPC3 that is needed for mGluR-dependent synaptic signaling in mouse cerebellar Purkinje cells. TRPC3 is the most abundantly expressed TRPC subunit in Purkinje cells...
August 14, 2008: Neuron
Naoko Adachi, Takeshi Kobayashi, Hideyuki Takahashi, Takumi Kawasaki, Yasuhito Shirai, Takehiko Ueyama, Toshio Matsuda, Takahiro Seki, Norio Sakai, Naoaki Saito
Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in protein kinase Cgamma (PKCgamma). Interestingly, 18 of 22 mutations are concentrated in the C1 domain, which binds diacylglycerol and is necessary for translocation and regulation of PKCgamma kinase activity. To determine the effect of these mutations on PKCgamma function and the pathology of SCA14, we investigated the enzymological properties of the mutant PKCgammas. We found that wild-type PKCgamma, but not C1 domain mutants, inhibits Ca2+ influx in response to muscarinic receptor stimulation...
July 11, 2008: Journal of Biological Chemistry
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