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ABSTRACT: Neurotrophin-3 (NT-3) plays numerous important roles in the CNS and the elevation of intracellular Ca(2+) ([Ca(2+)](i)) is critical for these functions of NT-3. However, the mechanism by which NT-3 induces [Ca(2+)](i) elevation remains largely unknown. Here, we found that transient receptor potential canonical (TRPC) 5 protein and TrkC, the NT-3 receptor, exhibited a similar temporal expression in rat hippocampus and cellular colocalization in hippocampal neurons. Stimulation of the neurons by NT-3 induced a nonselective cation conductance and PLCγ-dependent [Ca(2+)](i) elevation, which were both blocked when TRPC5, but not TRPC6 channels, were inhibited. Moreover, the Ca(2+) influx through TRPC5 induced by NT-3 inhibited the neuronal dendritic growth through activation of calmodulin-dependent kinase (CaMK) IIα. In contrast, the Ca(2+) influx through TRPC6 induced by NT-4 promoted the dendritic growth. Thus, TRPC5 acts as a novel and specific mediator for NT-3 to regulate dendrite development through CaMKIIα.
Journal of Neuroscience 07/2012; 32(27):9383-95. · 7.11 Impact Factor
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ABSTRACT: Intracellular Ca(2+) signaling plays critical roles in VEGF-mediated angiogenesis. Transient receptor potential canonical (TRPC) channel 6, a Ca(2+)-permeable non-selective cation channel, can be activated by VEGF. Here, we report that TRPC6 is important for VEGF-mediated angiogenesis. Inhibition of TRPC6 in human umbilical vein endothelial cells (HUVECs) by pharmacological or genetic approaches arrested HUVECs at G2/M phase and suppressed VEGF-induced HUVEC proliferation and tube formation. Furthermore, inhibition of TRPCs abolished VEGF-, but not FGF-induced angiogenesis in the chick embryo chorioallantoic membrane. These results suggest that TRPC6 plays an important role in VEGF-mediated angiogenesis.
Cancer letters 05/2009; 283(1):43-51. · 4.86 Impact Factor
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ABSTRACT: Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable, nonselective cation channels formed by homomeric or heteromeric complexes of TRPC proteins that contain six transmembrane domains. These channels can be activated through a phospholipase-C-dependent mechanism, making them sensors for environmental cues. Their expression begins early in embryonic days and remains in adulthood. These channels have important roles in the processes of neuronal development, including neural stem cell proliferation, cerebellar granule cell survival, axon path finding, neuronal morphogenesis, and synaptogenesis. In this review, we will discuss functional implications of TRPC channels during brain development.
Pflügers Archiv - European Journal of Physiology 12/2008; 458(2):283-9. · 4.46 Impact Factor
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ABSTRACT: The canonical transient receptor potential channels (TRPCs) are Ca(2+)-permeable nonselective cation channels with various physiological functions. Here, we report that TRPC6, a member of the TRPC family, promotes hippocampal neuron dendritic growth. The peak expression of TRPC6 in rat hippocampus was between postnatal day 7 and 14, a period known to be important for maximal dendritic growth. Overexpression of TRPC6 increased phosphorylation of Ca(2+)/calmodulin-dependent kinase IV (CaMKIV) and cAMP-response-element binding protein (CREB) and promoted dendritic growth in hippocampal cultures. Downregulation of TRPC6 by short hairpin RNA interference against TRPC6 suppressed phosphorylation of both CaMKIV and CREB and impaired dendritic growth. Expressing a dominant-negative form of CaMKIV or CREB blocked the TRPC6-induced dendritic growth. Furthermore, inhibition of Ca(2+) influx suppressed the TRPC6 effect on dendritic growth. Finally, in TRPC6 transgenic mice, the phosphorylation of CaMKIV and CREB was enhanced and the dendritic growth was also increased. In conclusion, TRPC6 promoted dendritic growth via the CaMKIV-CREB pathway. Our results thus revealed a novel role of TRPC6 during the development of the central nervous system (CNS).
Journal of Cell Science 08/2008; 121(Pt 14):2301-7. · 6.11 Impact Factor
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ABSTRACT: The transient receptor potential canonical (TRPC) channels are Ca2+-permeable, nonselective cation channels with different biological functions, but their roles in brain are largely unknown. Here we report that TRPC6 was localized to excitatory synapses and promoted their formation via a CaMKIV-CREB-dependent pathway. TRPC6 transgenic mice showed enhancement in spine formation, and spatial learning and memory in Morris water maze. These results reveal a previously unknown role of TRPC6 in synaptic and behavioral plasticity.
Nature Neuroscience 08/2008; 11(7):741-3. · 15.53 Impact Factor
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ABSTRACT: Channels formed by the transient receptor potential (TRP) family of proteins have a variety of physiological functions. Here we report that two members of the TRP cation channel (TRPC) subfamily, TRPC3 and 6, protected cerebellar granule neurons (CGNs) against serum deprivation-induced cell death in cultures and promoted CGN survival in rat brain. In CGN cultures, blocking TRPC channels or downregulating TRPC3 or 6 suppressed brain-derived neurotrophic factor (BDNF)-mediated protection, BDNF-triggered intracellular Ca2+ elevation and BDNF-induced CREB activation. By contrast, overexpressing TRPC3 or 6 increased CREB-dependent reporter gene transcription and prevented apoptosis in the neurons deprived of serum, and this protection was blocked by the dominant negative form of CREB. Furthermore, downregulating TRPC3 or 6 induced CGN apoptosis in neonatal rat cerebellum, and this effect was rescued by overexpressing either TRPC3 or 6. Thus, our findings provide in vitro and in vivo evidence that TRPC channels are important in promoting neuronal survival.
Nature Neuroscience 05/2007; 10(5):559-67. · 15.53 Impact Factor
