TRPC5 is a regulator of hippocampal neurite length and growth cone morphology

Greka, Anna; Navarro, Betsy; Oancea, Elena; Duggan, Anne; Clapham, David E.

doi:10.1038/nn1092

Cited by 351 publications

(326 citation statements)

References 42 publications

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“…high levels of TRPC1, 3, and 5 mRNA were found in cerebellum (28). Moreover, cultured hippocampal neurons express TRPC1 (16), TRPC5 (29), and TRPC6 3 proteins. Thus, selective co-assembly of TRPC subunits may occur in discrete brain regions.…”

Section: Discussionmentioning

confidence: 99%

Formation of Novel TRPC Channels by Complex Subunit Interactions in Embryonic Brain

Strübing¹,

Krapivinsky²,

Krapivinsky

et al. 2003

Journal of Biological Chemistry

388

312

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Mammalian short TRP channels (TRPCs) are putative receptor-and store-operated cation channels that play a fundamental role in the regulation of cellular Ca 2؉ homeostasis. Assembly of the seven TRPC homologs (TRPC1-7) into homo-and heteromers can create a large variety of different channels. However, the compositions as well as the functional properties of native TRPC complexes are largely undefined. We performed a systematic biochemical study of TRPC interactions in mammalian brain and identified previously unrecognized channel heteromers composed of TRPC1, TRPC4, or TRPC5 and the diacylglycerol-activated TRPC3 or TRPC6 subunits. The novel TRPC heteromers were found exclusively in embryonic brain. In heterologous systems, we demonstrated that assembly of these novel heteromers required the combination of TRPC1 plus TRPC4 or TRPC5 subunits along with diacylglycerolsensitive subunits in the channel complexes. Functional interaction of the TRPC subunits was verified using a dominant negative TRPC5 mutant (TRPC5 DN ). Co-expression of TRPC5 DN suppressed currents through TRPC5-and TRPC4-containing complexes; TRPC3-associated currents were unaffected by TRPC5 DN unless TRPC1 was also co-expressed. This complex assembly mechanism increases the diversity of TRPC channels in mammalian brain and may generate novel heteromers that have specific roles in the developing brain.Cellular Ca 2ϩ signaling is dependent on ubiquitously expressed receptor-and store-operated cation channels (ROCs 1 and SOCs). These channels mediate Ca 2ϩ influx in response to hormones and other stimuli that activate phospholipase C (PLC) isoenzymes (1-3). The widespread expression and functional diversity of ROCs and SOCs is reflected by the large variety of these channels with diverse biophysical properties and regulation mechanisms.There is growing evidence that members of the TRPC cation channel family can form ROCs and SOCs. Belonging to the larger superfamily of mammalian TRP channels, seven TRPCs (TRPC1-7) have been identified (4, 5). Heterologous expression of the highly homologous TRPC3, 6, and 7 gave rise to diacylglycerol (DAG)-activated ROCs (6, 7). TRPC1, 4, and 5 constitute a second structural TRPC subfamily. Whereas TRPC4 and TRPC5 were activated by an unknown PLC-dependent mechanism (8, 9), TRPC1 was characterized as a SOC (10). Other studies indicated that TRPC3, TRPC4, and TRPC5 might also contribute to SOCs activated by depletion of intracellular Ca 2ϩ stores (11)(12)(13)(14).Based on their structural similarity with voltage-dependent K ϩ channels, functional TRPC complexes are presumed to be tetramers. Many of the disparate results regarding TRPC function and regulation could be reconciled by assuming that TRPC subunits can assemble into heteromeric channels with diverse properties. Montell and co-workers demonstrated that TRPC1 and TPRC3 formed complexes based on co-immunoprecipitation studies of tagged proteins (15). We reported that TRPC1 co-assembled with TRPC4 and TRPC5 in rat brain (16). The biophysical properties of TRPC(1...

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Section: Discussionmentioning

confidence: 99%

Formation of Novel TRPC Channels by Complex Subunit Interactions in Embryonic Brain

Strübing¹,

Krapivinsky²,

Krapivinsky

et al. 2003

Journal of Biological Chemistry

388

312

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“…Another cationic channel that is activated by G protein-dependent receptors -the heteromeric TRPC1/TRPC5 channel -has been reported in axons of cultured hippocampal neurons 29 . These channels generate an inward current and might regulate the growth of axons in developing neurons 30 , but their precise function in mature axons remains largely unknown.…”

Section: Gap Junctionsmentioning

confidence: 99%

Information processing in the axon

2004

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“…Thus, the phosphoprotein stathmin, which is found in principal neurons where it contributes to microtubule dynamics and is necessary for TRPC5 transit in neurites (Greka et al, 2003), is highly expressed in areas controlling both learned and innate fear responses. Stathmin null mice showed deficits in both innate and conditioned fear (Shumyatsky et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…In constrast to common perception, TRP channels are not exclusive to sensory nerve endings, but are also present in epithelia as well as axons, cell bodies, and dendrites of neurons. TRPC proteins control growth cone movement in both mammalian and amphibian model systems (Bezzerides et al, 2004;Greka et al, 2003;Shim et al, 2005;Wang and Poo, 2005), but their function in synapses is not well understood. Most importantly, tetrameric TRPC and TRPV subunits form excitatory, nonselective, weakly voltage-gated ion channels that are greatly potentiated by phospholipase C linked receptors (Clapham, 2003;Clapham, 2007;Ramsey et al, 2006;Strübing et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Essential Role for TRPC5 in Amygdala Function and Fear-Related Behavior

RICCIO¹

2009

Journal of End-to-End-testing

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SummaryThe transient receptor potential channel 5 (TRPC5) is predominantly expressed in the brain where it can form heterotetrameric complexes with TRPC1 and TRPC4 channel subunits. These excitatory, non-selective cationic channels are regulated by G protein, phospholipase C-coupled receptors. Here, we show that TRPC5 −/− mice exhibit diminished innate fear levels in response to innately aversive stimuli. Moreover, mutant mice exhibited significant reductions in responses mediated by synaptic activation of Group I metabotropic glutamate and cholecystokinin 2 receptors in neurons of the amygdala. Synaptic strength at afferent inputs to the amygdala was diminished in P10-P13 null mice. In contrast, baseline synaptic transmission, membrane excitability, and spike timing-dependent longterm potentiation at cortical and thalamic inputs to the amygdala were largely normal in older null mice. These experiments provide genetic evidence that TRPC5, activated via G protein-coupled neuronal receptors, has an essential function in innate fear.

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TRPC5 is a regulator of hippocampal neurite length and growth cone morphology

Cited by 351 publications

References 42 publications

Formation of Novel TRPC Channels by Complex Subunit Interactions in Embryonic Brain

Formation of Novel TRPC Channels by Complex Subunit Interactions in Embryonic Brain

Information processing in the axon

Essential Role for TRPC5 in Amygdala Function and Fear-Related Behavior

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