TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway

Journal of Cell Science, Jul 2008

Yilin Tai, Shengjie Feng, Ruiliang Ge, Wanlu Du, Xiaoxing Zhang, Zhuohao He, Yizheng Wang

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TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway

Yilin Tai 1 Shengjie Feng 1 Ruiliang Ge 0 Wanlu Du 1 Xiaoxing Zhang 1 Zhuohao He 1 Yizheng Wang ) 1 0 Eastern Hepatobiliary Hospital , Shanghai, 200438 , Peoples Republic of China 1 Laboratory of Neural Signal Transduction, Institute of Neuroscience, Shanghai Institutes of Biological Sciences, State Key Laboratory of Neuroscience, The Graduate School, Chinese Academy of Science , 320 Yueyang Road, Shanghai 200031 , Peoples Republic of China - Summary The canonical transient receptor potential channels (TRPCs) are Ca2+-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 Ca2+/calmodulin-dependent kinase IV (CaMKIV) and cAMP-response-element binding protein ce (CREB) and promoted dendritic growth in hippocampal n cultures. Downregulation of TRPC6 by short hairpin RNA e ic interference against TRPC6 suppressed phosphorylation of both lS CaMKIV and CREB and impaired dendritic growth. le Expressing a dominant-negative form of CaMKIV or CREB C f o l a rn Introduction u The canonical transient receptor potential channels (TRPCs) are Jo nonselective cation channels that are expressed in a variety of multicellular organisms with different functions (Montell et al., 2002). The TRPC family can be divided by homology and function into four subfamilies: TRPC1, TRPC2, TRPC4/5 and TRPC3/6/7 (Clapham, 2003). They can form homomeric or heteromeric channels with distinct properties, such as current rectification and Ca2+ permeability (Clapham, 2003). Some TRPC proteins are expressed in the CNS and function as important regulators during development (Jia et al., 2007; Li et al., 1999). TRPC1 is mainly localized to dendritic processes of dopaminergic neurons (Martorana et al., 2006), whereas TRPC6 is localized to proximal dendrites and the axon hillock (Giampa et al., 2007). Interestingly, TRPC5 is preferentially localized to the neuronal nuclei in the substantia nigra (De March et al., 2006), and TRPC3 is mainly found in oligodendrocytes (Fusco et al., 2004). TRPC1 participates in basic fibroblast growth factor (bFGF)-dependent neural stem cell proliferation (Fiorio Pla et al., 2005). TRPC3 and TRPC6 are involved in brain-derived neurotrophic factor (BDNF)-mediated growth cone turning, neuron survival and spine formation (Amaral and Pozzo-Miller, 2007; Jia et al., 2007; Li et al., 2005). TRPC5 inhibits neurite outgrowth in hippocampal cultures (Greka et al., 2003). The establishment of dendritic morphology is critical for the development of neuronal circuits (Cline, 2001). Dendritic abnormalities are commonly associated with conditions resulting in mental retardation, such as Down syndrome (Becker et al., 1986) and Fragile X syndrome (Dierssen and Ramakers, 2006). A large blocked the TRPC6-induced dendritic growth. Furthermore, inhibition of Ca2+ 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). Supplementary material available online at http://jcs.biologists.org/cgi/content/full/121/14/2301/DC1 amount of evidence demonstrates that Ca2+ and its signaling control the development of dendrites (Redmond and Ghosh, 2005; Redmond et al., 2002; Wu and Cline, 1998). Elevation in intracellular Ca2+ concentration can lead to changes in dendritic morphology. The Ca2+ influx through either voltage-sensitive Ca2+ channels (VSCCs) or N-methyl-D-aspartate glutamate receptors (NMDARs) is important for activity-dependent dendritic growth (Redmond et al., 2002; Sin et al., 2002). Moreover, transcription factors are involved in the Ca2+-mediated changes in dendrite morphology (Aizawa et al., 2004; Gaudilliere et al., 2004; Redmond et al., 2002), among which, cAMP-response-element binding protein (CREB) is regulated by TRPC3 or TRPC6 (Jia et al., 2007). Since TRPCs are Ca2+permeable channels and their activation is less dependent on depolarization (Venkatachalam and Montell, 2007), we asked whether TRPC channels play a role in dendritic development. In the present study, we report that TRPC6 was highly expressed during the period of maximal dendritic growth and promoted dendritic growth through a CaMKIV-CREB-dependent pathway. TRPC6 transgenic mice showed upregulated phosphorylation of CaMKIV and CREB and more complicated dendrite structures. These findings revealed a novel role of TRPC6 during development of the CNS. Results Expression of TRPCs in rat hippocampus during development To explore the possible (...truncated)


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Yilin Tai, Shengjie Feng, Ruiliang Ge, Wanlu Du, Xiaoxing Zhang, Zhuohao He, Yizheng Wang. TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway, Journal of Cell Science, 2008, pp. 2301-2307, 121/14, DOI: 10.1242/jcs.026906