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)