Next Article in Journal
Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers
Next Article in Special Issue
TRP Channels Involved in Spontaneous L-Glutamate Release Enhancement in the Adult Rat Spinal Substantia Gelatinosa
Previous Article in Journal / Special Issue
Post-Translational Modifications of TRP Channels
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 3
Issue 2
10.3390/cells3020288
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity

by
Fang Zheng
1,* and
Kevin D. Phelan
2
1
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 611, Little Rock, AR 72205, USA
2
Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, Slot 846, Little Rock, AR 72205, USA
*
Author to whom correspondence should be addressed.
Cells 2014, 3(2), 288-303; https://doi.org/10.3390/cells3020288
Submission received: 28 February 2014 / Revised: 29 March 2014 / Accepted: 2 April 2014 / Published: 9 April 2014
(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels)
Browse Figures
Versions Notes

Abstract

:
Canonical transient receptor potential (TRPC) channels are a family of polymodal cation channels with some degree of Ca2+ permeability. Although initially thought to be channels mediating store-operated Ca2+ influx, TRPC channels can be activated by stimulation of Gq-coupled G-protein coupled receptors, or by an increase in intracellular free Ca2+ concentration. Thus, activation of TRPC channels could be a common downstream event of many signaling pathways that contribute to seizure and excitotoxicity, such as N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ influx, or metabotropic glutamate receptor activation. Recent studies with genetic ablation of various TRPC family members have demonstrated that TRPC channels, in particular heteromeric TRPC1/4 channels and homomeric TRPC5 channels, play a critical role in both pilocarpine-induced acute seizures and neuronal cell death. However, exact underlying mechanisms remain to be fully elucidated, and selective TRPC modulators and antibodies with better specificity are urgently needed for future research.

1. Introduction

Seizures arise from the synchronized burst firing of a large group of cortical neurons. Seizures can be induced by repetitive electric stimulations (i.e., kindling) of the perforant pathway in the hippocampus, or by chemical convulsants (e.g., the muscarinic agonist pilocarpine) that act on the hippocampal circuitry resulting in synchronized cortical firing. The hippocampus contains some of the neuronal populations that are most vulnerable to excitotoxicity, which is neuronal cell death caused by over-activation of glutamate receptors [1,2].
Excitotoxicity has emerged as a shared pathophysiological component of stroke, epilepsy and head trauma [2,3]. Minutes after the onset of ischemia, ATP in the severely affected core region is depleted, and all ATP-dependent processes that are critical to maintain normal function stop. Similarly, the depletion of ATP also occurs during intense seizures. Loss of ATP-dependent membrane transport results in the collapse of ion gradients across cell membranes thereby initiating a vicious cycle: accumulation of extracellular K+ leads to membrane depolarization, which in turn exacerbates energy deficits and further destabilizes ion gradients. The collapse of ion gradients also impairs clearance of glutamate from the synaptic cleft which floods the extracellular space with glutamate leading to widespread neuronal cell death.
Excessive Ca2+ influx is thought to trigger excitotoxicity [2]. The N-methyl-D-aspartate (NMDA) receptor, a subtype of ionotropic glutamate receptor with high calcium permeability, is thought to play a key role and was the first to be targeted for stroke therapy [4]. Although supported by many studies in animal models [4], clinical trials with NMDA antagonists all failed [5,6] suggesting that mechanisms underlying clinically relevant excitotoxicity are not yet fully understood. There are likely alternative signaling pathways leading to Ca2+ overload such as those involving metabotropic glutamate receptors (mGluRs), a family of G-protein coupled glutamate receptors [7].

2. The Role of Group I mGluRs in Seizure and Excitotoxicity

The group I mGluRs coupled to phospholipase C (i.e., mGluR1 and mGluR5) have been implicated in seizure and excitotoxicity [8,9,10]. The first mGluR selective agonist, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), induced limbic seizures and neuronal degeneration in vivo [8]. A selective group I mGluR agonist, (S)-3,5-dihydroxyphenylglycine (DHPG), had the same effect [10] indicating that the seizures and neuronal cell death induced by the broad-spectrum mGluR agonist 1S,3R-ACPD are likely mediated by group I mGluRs). The pattern of neurodegeneration induced by 1S,3R-ACPD [9] was similar to the neurodegeneration induced by kainic acid [11]. Two of the most vulnerable regions to the cell death caused by 1S,3R-ACPD are the hippocampal CA3 region and the lateral septum, both of which are highly vulnerable to limbic seizures induced by electrical kindling [12].
Why are the hippocampal CA3 region and lateral septum highly vulnerable to limbic seizures and excitotoxicity? In lateral septal neurons, mGluR agonists induce “epileptiform” burst firing with a large depolarizing plateau potential [13,14] that is similar to the “paroxysmal depolarization shift”. The plateau potential was triggered by membrane depolarization and was not blocked by tetrodotoxin [15]. Group I mGluR agonists induce similar burst firing in CA3 pyramidal neurons [8,16,17]. Under voltage-clamp recording, activation of mGluRs results in an inward current permeable to both sodium and calcium, with a negative slope region in their I-V relationship [18,19,20]. Therefore, this plateau potential is thought to be mediated by a Ca2+-activated non-selective (CAN) current. Inward membrane currents with a negative slope become greater in amplitude following membrane depolarization and subsequently generate additional depolarization. This positive feedback loop is capable of forming a self-regenerative plateau potential underlying the epileptiform burst firing observed in lateral septal neurons. Furthermore, the CAN-current in lateral septal neurons is a major source of Ca2+ influx that likely contributes to excitotoxicity [21].
The molecular identity of ion channels mediating the CAN current remained uncertain for years but the canonical transient receptor potential (TRPC) channels have emerged recently as the leading candidate [22]. The aim of this review is to summarize the recent data that support a role of TRPC channels in seizure and excitotoxicity and discuss the critical issues that need to be resolved in future studies.

3. Expression, Structure and Pharmacology of TRPC Channels

TRPCs are the mammalian homologues of drosophila trp channels. There are seven members (TRPC1-7) in the mammalian TRPC family (for review, see [23]). All but one of the TRPC genes have been identified in the human genome (TRPC2 is a pseudogene) and may contribute to various human diseases. Based on sequence homology and functional properties, the TRPC family can be divided into two subgroups: TRPC1/4/5 and TRPC3/6/7.
Structurally, the superfamily of TRP channels share a common architecture with voltage-gated potassium channels and calcium channels. All of the TRP family members have six putative transmembrane regions and a putative reentrance loop that forms the ion-conducting pore [24]. The transmembrane regions are flanked by an intracellular amino-terminal domain and an intracellular carboxyl-terminal domain. Ion channels with this type of architecture are typically tetrameric, i.e., formed by four subunits. A recent study of TRPV1 supports the structural similarity between the trp channels and potassium channels [25] but the structure of TRPC channels remains to be determined.
At the present time, our knowledge regarding the expression of TRPC channels in the central nervous system has relied largely on in situ hybridization of TRPC mRNAs. Among 7 members of the TRPC family, TRPC1 is ubiquitously expressed while other TRPC family members have a more discrete expression pattern in the brain [26,27]. Moderate to high expression of TRPC1 can be detected in most limbic areas. Expression of TRPC2, a pseudogene in humans, is mainly limited to the olfactory bulbs in rodents [26,27]. TRPC3 expression is most prominent in the cerebellum [26,28,29]. TRPC4 is highly expressed in the lateral septum and the CA1 region of the hippocampus [30,31,32,33]. TRPC5 is highly expressed in the CA1-CA3 region of the hippocampus and the amygdala [34,35]. TRPC6 is highly expressed in the dentate gyrus [36]. TRPC7 (originally named TRP7) mRNA has been detected at moderate to low levels in the olfactory bulbs, cerebellum, and dentate gyrus [37]. Commercial antibodies against various members of the TRPC family have not all been validated using TRPCKO mice. The specificity of commercial antibodies against TRPC4 has been questioned [38]. A commercial TRPC7 antibody (Santa Cruz) is actually generated specifically against a TRP now known as TRPM2 [39]. The lack of specific antibodies at the present time is a huge roadblock for the study of neuronal TRPC channels, and there is an urgent need for the development and specificity validation of antibodies against most TRPC family members.
All TRP channels are cation channels with various permeability ratios for calcium and sodium. Functional TRPC channels are thought to be either homomeric or heteromeric channels formed by members in the same subgroup [35,40,41]. For example, TRPC1 can form homomeric channels by itself or heteromeric channels with TRPC4 or TRPC5 in an artificial expression system. However, interactions between TRPCs from different subgroups have been reported [42,43]. These reported interactions need to be viewed with skepticism until the specificity of the TRPC antibodies are confirmed using TRPC knockout mice. The exact gating mechanism for TRPC channels remains hotly debated. TRPC1, 4 and 5 channels have been proposed to function as store-operated channels [26,30,34,44], and they interact directly with stim1, a recently identified molecular sensor for store depletion [45]. However, recent studies have shown that the gating of TRPC channels comprised of TRPC1/4/5 is “polymodal” since they can be activated by stimulation of G-protein coupled receptors, such as mGluR1 [46], or by a rise of intracellular free Ca2+ directly [22,47]. Importantly, this calcium sensitivity allows TRPC channels comprised of TRPC1/4/5 to amplify calcium signaling. TRPC3, 6, and 7 channels, on the other hand, do not directly interact with stim1 [45] but are instead directly activated by diacylglycerol [48]. In summary, there are many controversies and questions regarding the subunit composition and functional properties of TRPC channels. Data obtained from artificial expression systems need to be assessed in native biological systems using genetic knockout approaches.
Few selective drugs for TRPC channels have been discovered. SKF96365 inhibits all TRPC channels, but is considered to be nonspecific since it also inhibits other ion channels [49,50]. La3+ blocks most TRPC channels with the exception of channels containing TRPC4 or TRPC5. Acting on three glutamate residues shared by TRPC4 and TRPC5, La3+ activates the homomeric TRPC4 and TRPC5 channels and heteromeric TRPC1/5 channels [35,51]. Presumably, heteromeric TRPC1/4 channels should also be potentiated by La3+. However, the native TRPC4 current that was eliminated in TRPC4 knockout (KO) mice was blocked by low micromolar La3+ [52]. A recent study has suggested that ML204 is a selective inhibitor of TRPC4 [53], however, it is ineffective against native TRPC4 containing channels in lateral septal neurons [54]. Pyr-3 has been reported as a selective inhibitor of TRPC3 channels [55] but its selectivity remains to be confirmed in TRPC3KO mice. Recent drug screening studies have identified a few compounds that apparently act against TRPC6 [56,57,58,59,60] though only one of these compounds (hyperforin) has been tested in TRPC6 KO mice with apparent mixed results. Ding et al [59] demonstrated the absence of hyperforin induced constriction of aortic segments in TRPC6KO mice, while Chen et al. [60] reported attenuation, but not complete blockade of hyperforin induced microvascular leakage in TRPCKO mice. In summary, there are no drugs that target TRPC channels with confirmed specificity that would allow them to be used as pharmacological tools to investigate the functional roles of specific TRPC channels. At the present time, functional studies of neuronal TRPC channels must rely on targeted genetic ablation. Global disruption of a gene through development could have unintended consequences. The use of inducible or tissue-specific genetic approaches would be preferable.

4. TRPC Channels, the Ca2+-Activated Non-Selective (CAN) Current and Epileptiform Burst Firing in the Lateral Septum

As mentioned earlier, the expression level of TRPC4 is the highest in the lateral septum, a limbic relay nucleus. In lateral septal neurons, mGluR agonists induce “epileptiform” burst firing with a large depolarizing plateau potential similar to the “paroxysmal depolarization shift” [13,14]. To determine whether this plateau potential is mediated by TRPC channels, we and others recorded from lateral septal neurons in a panel of TRPC KO mice [33,54]. The plateau potential is altered in TRPC1KO mice and is totally absent in TRPC4KO and TRPC1/4 double knockout (DKO) mice, but is normal in TRPC3KO, TRPC5KO, TRPC6KO, and TRPC7KO mice (Figure 1) [33]. These observations indicate the involvement of TRPC1 and TRPC4 in the mGluR1/5-mediated plateau potential and rule out the involvement of TRPC3, 5, 6, and 7. Our data also suggest that the TRPC channels responsible for the plateau potential are likely heteromeric TRPC1/4 channels.
Cells 03 00288 g001 1024
Figure 1. Quantitative comparison of the 1S,3R-ACPD-induced plateau potential in lateral septal neurons in WT and TRPC KO mice. (A) Representative traces showing the normal decay of the membrane potential after spikes generated by a brief depolarizing current pulse under control conditions and the plateau potential after spikes generated by the same depolarizing current pulse following bath perfusion of 30 µM 1S,3R-ACPD. The area-under-the curve (area; shaded) was measured from the end of the depolarizing current pulse to a time point after the end of the plateau potential (typically 1 or 2 s). The mean of total area (shaded with both light and dark gray) in the presence of 1S,3R-ACPD for each lateral septal neuron was plotted in B; (B) The total area in the presence of 1S,3R-ACPD in WT, TRPC1KO, TRPC1/4DKO, TRPC3KO, TRPC5KO, TRPC6KO, TRPC7KO (n = 34, 36, 9, 10, 6, 7, 9 respectively). Note that the TRPC1KO and TRPC1/4DKO groups were significantly different from the WT group (***: p < 0.001, Kruskal-Wallis test and Dunn's Multiple Comparison Test). Traces in A adapted from Figure 3B of [33]. The WT, TRPC1KO and TRPC1/4DKO data in B are replotted from the raw data presented in Figure 3C of [33]. The TRPC3KO, TRPC5KO and TRPC6KO data were reported in [33]. TRPC7KO data is unpublished data that was obtained in a similar manner.
Figure 1. Quantitative comparison of the 1S,3R-ACPD-induced plateau potential in lateral septal neurons in WT and TRPC KO mice. (A) Representative traces showing the normal decay of the membrane potential after spikes generated by a brief depolarizing current pulse under control conditions and the plateau potential after spikes generated by the same depolarizing current pulse following bath perfusion of 30 µM 1S,3R-ACPD. The area-under-the curve (area; shaded) was measured from the end of the depolarizing current pulse to a time point after the end of the plateau potential (typically 1 or 2 s). The mean of total area (shaded with both light and dark gray) in the presence of 1S,3R-ACPD for each lateral septal neuron was plotted in B; (B) The total area in the presence of 1S,3R-ACPD in WT, TRPC1KO, TRPC1/4DKO, TRPC3KO, TRPC5KO, TRPC6KO, TRPC7KO (n = 34, 36, 9, 10, 6, 7, 9 respectively). Note that the TRPC1KO and TRPC1/4DKO groups were significantly different from the WT group (***: p < 0.001, Kruskal-Wallis test and Dunn's Multiple Comparison Test). Traces in A adapted from Figure 3B of [33]. The WT, TRPC1KO and TRPC1/4DKO data in B are replotted from the raw data presented in Figure 3C of [33]. The TRPC3KO, TRPC5KO and TRPC6KO data were reported in [33]. TRPC7KO data is unpublished data that was obtained in a similar manner.
Cells 03 00288 g001
It should be noted that the mGluR agonist-induced plateau potential is present in a small group of lateral septal neurons in TRPC1KO mice, suggesting that homomeric TRPC4 channels are capable of mediating the plateau potential [33]. The remaining question is why a plateau potential is only observed in a small group of lateral septal neurons. It appears that the presence of TRPC1 may be critical to the coupling between mGluR1/5 and TRPC channels though the exact molecular mechanism for such a requirement remains to be determined.
Although sharing sensitivity to SKF96365, the pharmacological properties of TRPC channels that mediate the plateau potential in lateral septal neurons appear to be distinct from the homomeric recombinant TRPC4 channels. First, La3+ exhibited only inhibitory effects on the plateau potential in lateral septal neurons [61] whereas it potentiates recombinant homomeric TRPC4 channels. Second, ML204, a reported selective inhibitor of recombinant homomeric TRPC4 channels, yielded inconsistent results against the plateau potential in lateral septal neurons ([54] which was attributed to possible degradation of ML204 in aqueous solutions. However, our personal experience suggests that this is not the case. We observed that in a single lateral septal neuron, ML204 blocks the plateau potential at 20 µM but is ineffective at 50 µM, suggesting complex pharmacological actions of ML204 on heteromeric TRPC1/4 channels [61]. Further investigation of the pharmacological properties of native TRPC1/4 channels in lateral septal neurons is needed to reach a definitive conclusion.
Figure 2 summarizes our current understanding regarding the underlying molecular mechanisms of mGluR agonist-induced epileptiform burst firing in lateral septal neurons. Group I mGluRs (mGluR1 and mGluR5) are both involved since specific negative allosteric modulators of mGluR1 and mGluR5 (CPCCOEt and MPEP, respectively) [62] can abolish the epileptiform burst firing induced by DHPG or 1S,3R-ACPD. It is possible that mGluR1 and mGluR5 may form heterodimers in lateral septal neurons since CPCCOEt and MPEP can block mGluR agonist-induced bursting in the same lateral septal neuron [33]. Downstream of activation of mGluR1 and 5, activation of phospholipase C (PLC) is also required because the epileptiform burst can be abolished by U73122, a selective PLC inhibitor [63]. Heteromeric TRPC1/4 channels are then activated by this signaling cascade, leading to the plateau potential underlying the epileptiform burst.
Cells 03 00288 g002 1024
Figure 2. The signaling cascade leading to epileptiform burst firing in lateral septal neuron.
Figure 2. The signaling cascade leading to epileptiform burst firing in lateral septal neuron.
Cells 03 00288 g002

5. TRPC Channels and Epileptiform Burst Firing in the Hippocampus

Kandel and Spencer [64] observed three types of firing patterns in hippocampal pyramidal neurons: single spikes, short bursts, and long-lasting bursts (100–200 ms). The long-lasting bursts were regarded as the cellular equivalents of interictal discharges and are defined as epileptiform burst firing. There has been a long standing debate about the underlying mechanism for the plateau potential associated with epileptiform burst firing [65]: some investigators suggest that it is generated by a neural network and requires activation of NMDA receptors; others suggest that it reflects a change in intrinsic membrane properties and is mediated by a persistent Na+ current [66], low-threshold voltage-gated calcium channels [67,68], or a CAN current [69]. Since TRPC4 and 5 are well expressed in the hippocampus, TRPC channels comprised of TRPC1/4/5 may play a critical role in epileptiform burst firing.
We recorded CA1 pyramidal neurons using the current-clamp intracellular recording method, and induced spontaneous epileptiform burst firing by bath application of 1S,3R-ACPD, a mGluR agonist known to induce seizures in vivo. We showed that in TRPC1KO mice and TRPC1/4DKO mice, mGluR agonist-induced spontaneous burst firing in CA1 pyramidal neurons was significantly reduced [70], and what remained were short bursts with an average of 3 spikes, which may be mediated by T-type or R-type voltage-gated Ca2+ channels [67,68]. In contrast, TRPC5KO mice exhibit normal mGluR agonist-induced epileptiform burst firing [70]. This came as a surprise since several groups suggested that TRPC5 contributes to the plateau potential [71,72,73]. Thus, our data suggest that TRPC1/4 channels play a critical role in the epileptiform burst firing in CA1 pyramidal neurons paralleling the functional role of these channels in lateral septal neurons as summarized in Figure 2.
Using the same panel of TRPC knockout mice, we also examined the role of TRPC1/4 channels in the epileptiform burst firing in CA3 pyramidal neurons. Spontaneous epileptiform burst firing can be induced in CA3 pyramidal neurons by bath application of bicuculline for 30 min [74] or by high-frequency stimulation of the mossy fiber pathway [75]. Although Wong and colleagues have proposed that the CAN current is the underlying mechanism for the plateau potential in CA3 pyramidal neurons [17], others have shown that the burst firing is synaptic in origin and reflects enhanced synaptic strength at recurrent collateral synapses via NMDA receptor-dependent long-term potentiation (LTP) [74,75]. TRPC5 may play a critical role in the mGluR5-dependent enhancement of NMDA-receptor-dependent LTP at CA3 recurrent collateral synapses. Future studies are needed to validate this hypothesis and pinpoint the exact role of TRPC5 in the generation of epileptiform burst firing in CA3 pyramidal neurons.

6. The Role of TRPC1, 4, 5 in Seizure and Excitotoxicity in Vivo

The full extent and range of potential contribution of TRPC channels to seizure and excitotoxicity can only be assessed in vivo. We studied the role of TRPC channels in seizure susceptibility and seizure-induced neuronal cell death, using the pilocarpine-induced status epilepticus model (Figure 3). The dramatic reduction of epileptiform burst firing at the cellular level in CA1 in TRPC1KO and TRPC1/4DKO mice failed to lead to a reduction of pilocarpine-induced acute seizures [33]. On the other hand, the normal epileptiform bursting in CA1 in TRPC5KO in vitro is associated with a significant reduction in the severity of pilocarpine-induced seizures in vivo [70]. Since TRPC1KO mice and TRPC1/4DKO mice show normal severity of pilocarpine-induced seizures (Figure 3), homomeric TRPC5 channels are likely involved in pilocarpine-induced acute seizures, not heteromeric channels such as TRPC1/4, TRPC1/5 or TRPC1/4/5.
Cells 03 00288 g003 1024
Figure 3. Pilocarpine-induced seizures were significantly reduced in TRPC5KO mice. The time course of pilocarpine-induced seizures in WT, TRPC1KO, TRPC1/4DKO, and TRPC5KO mice after a single injection of pilocarpine (280 mg/kg, i.p.). Pooled data (mean ± SEM) was plotted (n = 18, 14, 6, 19 for WT, TRPC1KO, TRPC1/4DKO and TRPC5KO mice). See Phelan et al. 2012 for description of seizure scale. Note significantly reduced seizure scores in TRPC5KO mice at the late phase after pilocarpine injection (***: p < 0.001, Two-way ANOVA; *: p < 0.05; **: p < 0.01, Bonferroni post hoc tests against WT). The TRPC1KO and TRPC5KO data are adapted from Figure 2 of [70], while the TRPC1/4KO data is from Figure 4A of [33].
Figure 3. Pilocarpine-induced seizures were significantly reduced in TRPC5KO mice. The time course of pilocarpine-induced seizures in WT, TRPC1KO, TRPC1/4DKO, and TRPC5KO mice after a single injection of pilocarpine (280 mg/kg, i.p.). Pooled data (mean ± SEM) was plotted (n = 18, 14, 6, 19 for WT, TRPC1KO, TRPC1/4DKO and TRPC5KO mice). See Phelan et al. 2012 for description of seizure scale. Note significantly reduced seizure scores in TRPC5KO mice at the late phase after pilocarpine injection (***: p < 0.001, Two-way ANOVA; *: p < 0.05; **: p < 0.01, Bonferroni post hoc tests against WT). The TRPC1KO and TRPC5KO data are adapted from Figure 2 of [70], while the TRPC1/4KO data is from Figure 4A of [33].
Cells 03 00288 g003
Cells 03 00288 g004 1024
Figure 4. A working hypothesis for TRPC5 in seizure and excitotoxicity. We propose that TRPC5 is critical for mGluR1/mGluR5-mediated enhancement of NMDA receptor-dependent long-term potentiation at SC synapses in CA1 and RC synapses in CA3. The enhanced LTP at SC synapses contributes to hyperexcitability and excitotoxicity in CA1 while enhanced LTP at RC synapses in CA3 contributes to the initiation of seizure and excitotoxicity in CA3. EC: entorhinal cortex; DG: dentate gyrus; MF: mossy fiber; RC: recurrent collaterals; SC: Schaffer collaterals; Sub: subiculum.
Figure 4. A working hypothesis for TRPC5 in seizure and excitotoxicity. We propose that TRPC5 is critical for mGluR1/mGluR5-mediated enhancement of NMDA receptor-dependent long-term potentiation at SC synapses in CA1 and RC synapses in CA3. The enhanced LTP at SC synapses contributes to hyperexcitability and excitotoxicity in CA1 while enhanced LTP at RC synapses in CA3 contributes to the initiation of seizure and excitotoxicity in CA3. EC: entorhinal cortex; DG: dentate gyrus; MF: mossy fiber; RC: recurrent collaterals; SC: Schaffer collaterals; Sub: subiculum.
Cells 03 00288 g004
The underlying mechanism of TRPC5 contribution to pilocarpine-induced acute seizures has yet to be elucidated. Our current hypothesis is that homomeric TRPC5 channels located in or near dendritic spines, are activated by Group I mGluRs and amplify the dendritic calcium signals thereby enhancing NMDA receptor-dependent LTP (Figure 4). This mechanism would apply to both Schaffer collateral-CA1 synapses and CA3 recurrent collateral synapses. Alternatively, TRPC5 channels may directly contribute to the plateau potential underlying spontaneous epileptiform burst firing in CA3 pyramidal neurons. TRPC5 channels may also be expressed at the presynaptic terminals and linked to neurotrophic factor receptors [76] where they play a role in synaptic plasticity. More intriguingly, there is evidence that the surface expression of TRPC5 may be dynamically regulated [72]. It is possible that the pilocarpine-induced acute seizures may result from increased surface expression of TRPC5 channels within different components of the cortical circuitry. Future studies are needed to test these hypotheses and elucidate the underlying mechanisms of TRPC5’s role in acute seizures.
Cells 03 00288 g005 1024
Figure 5. Neuronal cell death after pilocarpine-induced seizures in the hippocampus of WT, TRPC1KO, TRPC1/4DKO and TRPC5KO mice. Neuronal cell death induced by pilocarpine-induced seizures was assessed in selected groups of mice with comparable average seizure scores above three for WT (3.79 ± 0.14, n = 6), TRPC1KO (3.89 ± 0.13, n = 6), TRPC1/4DKO (3.89 ± 0.20, n = 5), and TRPC5KO mice (3.45 ± 0.10, n = 5). Serial coronal sections (50 µm) from mice with similar pilocarpine-induced seizures were stained with Nissl and surviving neurons (with stained cytoplasm and round nuclei) were counted using Stereologer with a 100X oil-immersion objective. The percentage of surviving neurons was calculated by dividing the cell count in each pilocarpine-treated mouse with the averaged cell count in WT control mice (mice without seizures). There was no significant difference in the number of neurons between WT and untreated KO mice. Pooled data (mean ± SEM) were plotted. Note the significant increase in surviving neurons in the CA1 region of TRPC1/4DKO and TRPC5KO (**: p < 0.01, ANOVA), and the significant increase in surviving neurons in the CA3 region of TRPC1/4DKO (*: p < 0.05, ANOVA). Adapted from data presented in Figure 6 of [33] and Figure 4 of [70] relative to untreated WT mice.
Figure 5. Neuronal cell death after pilocarpine-induced seizures in the hippocampus of WT, TRPC1KO, TRPC1/4DKO and TRPC5KO mice. Neuronal cell death induced by pilocarpine-induced seizures was assessed in selected groups of mice with comparable average seizure scores above three for WT (3.79 ± 0.14, n = 6), TRPC1KO (3.89 ± 0.13, n = 6), TRPC1/4DKO (3.89 ± 0.20, n = 5), and TRPC5KO mice (3.45 ± 0.10, n = 5). Serial coronal sections (50 µm) from mice with similar pilocarpine-induced seizures were stained with Nissl and surviving neurons (with stained cytoplasm and round nuclei) were counted using Stereologer with a 100X oil-immersion objective. The percentage of surviving neurons was calculated by dividing the cell count in each pilocarpine-treated mouse with the averaged cell count in WT control mice (mice without seizures). There was no significant difference in the number of neurons between WT and untreated KO mice. Pooled data (mean ± SEM) were plotted. Note the significant increase in surviving neurons in the CA1 region of TRPC1/4DKO and TRPC5KO (**: p < 0.01, ANOVA), and the significant increase in surviving neurons in the CA3 region of TRPC1/4DKO (*: p < 0.05, ANOVA). Adapted from data presented in Figure 6 of [33] and Figure 4 of [70] relative to untreated WT mice.
Cells 03 00288 g005
Figure 5 summarizes the extent of pilocarpine-induced neurodegeneration in different subfields of the hippocampus. A previous study suggested that TRPC1 plays a critical role in glutamate-induced excitotoxicity in the hippocampus in slice cultures [77]. However, we failed to detect any significant reduction in pilocarpine-induced neuronal cell death in the hippocampus in TRPC1KO mice. The seizure-induced neuronal cell death is reduced significantly in the CA1 and lateral septum in TRPC1/4DKO mice [33], and this reduction corresponds well with the epileptiform burst firing mediated by TRPC1/4 channels in those brain regions [33]. Pilocarpine-induced neuronal cell death in TRPC5KO mice is also significantly reduced in the CA1 area, but there is some variability in the CA3 area. It should be noted that the neuronal cell death in the hilar region is not significantly reduced by genetic ablation of TRPC1, 4 or 5.

7. Do TRPC3, 6, or 7 Play a Role in Seizure and Excitotoxicity?

This review has mostly focused on the role of the TRPC1/4/5 subgroup in seizure-induced neuronal cell death. The contribution of TRPC3/6/7 subgroup to seizure and excitotoxicity has yet to be fully elucidated, but there is some evidence in favor of such a role. Neuronal TRPC3 channels, for example, are activated by brain-derived neurotrophic factor (BDNF) via trk B receptors and are required for a very slow depolarization in hippocampal pyramidal neurons [78]. Since TRPC3 is a downstream effector of BDNF-trkB signaling pathway that is thought to play a role in epilepsy, one would expect that TRPC3 should play a significant role in pilocarpine-induced seizures and neuronal cell death. The highest expression level of TRPC6 is detected in dentate granule (DG) cells. Since the mossy fiber (the afferent of DG cells) often undergoes sprouting during epileptogenesis, one might expect that TRPC6 would play an important role in the generation of seizures. We are currently investigating the role of TRPC3, 6, and 7 in the hippocampal circuitry and hopefully these studies will yield mechanistic insights regarding the generation and propagation of pilocarpine-induced acute seizures. Furthermore, TRPC3, 6, and 7 may also be involved in modulating excitotoxicity. Recent studies suggest that TRPC3 and TRPC6 may have opposite roles: Activation of TRPC3 channels contributes to excitotoxicity whereas activation of TRPC6 reduces excitotoxicity [79,80,81]. However, further studies are needed to confirm these findings since the specificity of drugs targeting TRPC3 and TRPC6 used in these studies remains questionable.

8. Conclusions

TRPC channels have emerged as important players in seizure and excitotoxicity: Heteromeric TRPC1/4 channels clearly play a role in excitotoxicity in the lateral septum and the CA1 area of the hippocampus; homomeric TRPC5 channels appear to play a critical role in the generation of seizures as well as excitotoxicity. Members of the TRPC3/6/7 subgroup also may contribute to both, although the underlying mechanisms have yet to be fully delineated. TRPC channels are now viewed as highly promising molecular targets for developing novel therapeutic drugs for stroke, epilepsy and head trauma. Although recent progress in drug developments has been made, a truly selective drug against any TRPC channels has yet to emerge. The wide expression of some TRPC members such as TRPC1 also complicates the matter as TRPC1 expression in different cell populations may have distinct and contradictory roles. Thus, further comprehensive studies of the functional roles of TRPC family members are critical for future drug development.

Acknowledgments

This work was supported by National Institute of Neurological Disorders and Stroke [NS050381, NS047546]; the University of Arkansas for Medical Sciences Tobacco Research Fund and the University of Arkansas for Medical Sciences Hornick Research Award.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Olney, J.W. Brain lesion, obesity and other disturbances in mice treated with monosodium glutamate. Science 1969, 164, 719–721. [Google Scholar]
  2. Choi, D.W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988, 1, 623–634. [Google Scholar] [CrossRef]
  3. Lipton, S.A.; Rosenberg, R.A. Mechanisms of disease: Excitatory amino acids as a final common pathway in neurologic disorders. N. Engl. J. Med. 1994, 330, 613–622. [Google Scholar] [CrossRef]
  4. Kemp, J.A.; McKernan, R.M. NMDA receptor pathways as drug targets. Nat. Neurosci. 2002, 5, 1039–1042. [Google Scholar] [CrossRef]
  5. Davis, S.M.; Lees, K.R.; Albers, G.W.; Diener, H.C.; Markabi, S.; Karlsson, G.; Norris, J. Selfotel in acute ischemic stroke: Possible neurotoxic effects of an NMDA antagonist. Stroke 2000, 31, 347–354. [Google Scholar] [CrossRef]
  6. Lees, K.R.; Asplund, K.; Carolei, A.; Davis, S.M.; Diener, H.C.; Kaste, M.; Orgogozo, J.M.; Whitehead, J. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: A randomised controlled trial. GAIN International Investigators. Lancet 2000, 355, 1949–1954. [Google Scholar] [CrossRef]
  7. Pin, J.P.; Conn, P.J. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205–237. [Google Scholar] [CrossRef]
  8. Sacaan, A.I.; Schoepp, D.D. Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage. Neurosci. Lett. 1992, 139, 77–82. [Google Scholar] [CrossRef]
  9. McDonald, J.W.; Fix, A.S.; Tizzano, J.P.; Schoepp, D.D. Seizures and brain injury in neonatal rats induced by 1S, 3R-ACPD, a metabotropic glutamate receptor agonist. J. Neurosci. 1993, 13, 4445–4455. [Google Scholar]
  10. Barton, M.E.; Shannon, H.E. Behavioral and convulsant effects of the (S) enantiomer of the group I metabotropic glutamate receptor agonist 3,5-DHPG in mice. Neuropharmacology 2005, 48, 779–787. [Google Scholar] [CrossRef]
  11. Lothman, E.W.; Collins, R.C. Kainic acid induced limbic seizures: Metabolic, behavioral, electroencephalographic and neuropathological correlates. Brain Res. 1981, 218, 299–318. [Google Scholar] [CrossRef]
  12. Kliot, M.; Poletti, C.E. Hippocampal afterdischarges: differential spread of activity shown by the [14C]deoxyglucose technique. Science 1979, 204, 641–643. [Google Scholar]
  13. Zheng, F.; Gallagher, J.P. Trans-ACPD (trans-D,L-1-amino-1,3-cyclopentane-dicarboxylic acid) elicited oscillation of membrane potentials in rat dorsolateral septal nucleus neurons recorded intracellularly in vitro. Neurosci. Lett. 1991, 125, 147–150. [Google Scholar] [CrossRef]
  14. Zheng, F.; Gallagher, J.P. (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced burst firing is mediated by a native pertussis toxin-sensitive metabotropic receptor at rat dorsolateral septal nucleus neurons. Neuroscience 1995, 68, 423–434. [Google Scholar] [CrossRef]
  15. Zheng, F.; Gallagher, J.P. Burst firing of rat septal neurons induced by 1S,3R-ACPD requires influx of extracellular calcium. Eur. J. Pharmacol. 1992, 211, 281–282. [Google Scholar] [CrossRef]
  16. Rutecki, P.A.; Yang, Y. Metabotropic glutamate receptor activation modulates epileptiform activity in the hippocampus. Neuroscience 1997, 81, 927–935. [Google Scholar] [CrossRef]
  17. Chuang, S.C.; Zhao, W.; Young, S.R.; Conquet, F.; Bianchi, R.; Wong, R.K. Activation of group I mGluRs elicits different responses in murine CA1 and CA3 pyramidal cells. J. Physiol. 2002, 541, 113–121. [Google Scholar] [CrossRef]
  18. Caeser, M.; Brown, D.A.; Gahwiler, B.H.; Knopfel, T. Characterization of a calcium-dependent current generating a slow afterdepolarization of CA3 pyramidal cells in rat hippocampal slice cultures. Eur. J. Neurosci. 1993, 5, 560–569. [Google Scholar] [CrossRef]
  19. Raggenbass, M.; Pierson, P.; Metzger, D.; Alberi, S. Action of a metabotropic glutamate receptor agonist in rat lateral septum: Induction of a sodium-dependent inward aftercurrent. Brain Res. 1997, 776, 75–87. [Google Scholar] [CrossRef]
  20. Luthi, A.; Gahwiler, B.H.; Gerber, U. 1S,3R-ACPD induces a region of negative slope conductance in the steady-state current-voltage relationship of hippocampal pyramidal cells. J. Neurophysiol. 1997, 77, 221–228. [Google Scholar]
  21. Zheng, F.; Gallagher, J.P.; Connor, J.A. Activation of a metabotropic glutamate receptor potentiates spike-driven calcium increases in neurons of the dorsolateral septum. J. Neurosci. 1996, 16, 6079–6088. [Google Scholar]
  22. Gee, C.E.; Benquet, P.; Gerber, U. Group I metabotropic glutamate receptors activate a calcium-sensitive transient receptor potential-like conductance in rat hippocampus. J. Physiol. 2003, 546, 655–664. [Google Scholar] [CrossRef]
  23. Vazquez, G.; Wedel, B.J.; Aziz, O.; Trebak, M.; Putney, J.W. The mammalian TRPC cation channels. Biochim. Biophys. Acta 2004, 1742, 21–36. [Google Scholar]
  24. Pedersen, S.F.; Owsianik, G.; Nilius, B. TRP channels: An overview. Cell Calcium 2005, 38, 233–252. [Google Scholar] [CrossRef]
  25. Liao, M.; Cao, E.; Julius, D.; Cheng, Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 2013, 504, 107–112. [Google Scholar] [CrossRef]
  26. Zhu, X.; Jiang, M.; Peyton, M.; Boulay, G.; Hurst, R.; Stefani, E.; Birnbaumer, L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell 1996, 85, 661–671. [Google Scholar] [CrossRef]
  27. Yildirim, E.; Birnbaumer, L. TRPC2: Molecular biology and functional importance. Handb. Exp. Pharmacol. 2007, 179, 53–75. [Google Scholar] [CrossRef]
  28. Riccio, A.; Medhurst, A.D.; Mattei, C.; Kelsell, R.E.; Calver, A.R.; Randall, A.D.; Benham, C.D.; Pangalos, M.N. mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res. Mol. Brain Res. 2002, 109, 95–104. [Google Scholar] [CrossRef]
  29. Hartmann, J.; Dragicevic, E.; Adelsberger, H.; Henning, H.A.; Sumser, M.; Abramowitz, J.; Blum, R.; Dietrich, A.; Freichel, M.; Flockerzi, V.; et al. TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 2008, 59, 392–398. [Google Scholar] [CrossRef]
  30. Philipp, S.; Cavalie, A.; Freichel, M.; Wissenbach, U.; Zimmer, S.; Trost, C.; Marquart, A.; Murakami, M.; Flockerzi, V. A mammalian capacitative calcium entry channel homologous to Drosophila TRP and TRPL. EMBO J. 1996, 15, 6166–6171. [Google Scholar]
  31. Mori, Y.; Takada, N.; Okada, T.; Wakamori, M.; Imoto, K.; Wanifuchi, H.; Oka, H.; Oba, A.; Ikenaka, K.; Kurosaki, T. Differential distribution of TRP Ca2+ channel isoforms in mouse brain. Neuroreport 1998, 9, 507–515. [Google Scholar]
  32. Zechel, S.; Werner, S.; von Bohlen und Halbach, O. Distribution of TRPC4 in developing and adult murine brain. Cell Tissue Res. 2007, 328, 651–656. [Google Scholar] [CrossRef]
  33. Phelan, K.D.; Mock, M.M.; Kretz, O.; Shwe, U.T.; Kozhemyakin, M.; Greenfield, L.J.; Dietrich, A.; Birnbaumer, L.; Freichel, M.; Flockerzi, V.; et al. Heteromeric canonical transient receptor potential 1 and 4 channels play a critical role in epileptiform burst firing and seizure-induced neurodegeneration. Mol. Pharmacol. 2012, 81, 384–392. [Google Scholar] [CrossRef]
  34. Philipp, S.; Hambrecht, J.; Braslavski, L.; Schroth, G.; Freichel, M.; Murakami, M.; Cavalie, A.; Flockerzi, V. A novel capacitative calcium entry channel expressed in excitable cells. EMBO J. 1998, 17, 4274–4282. [Google Scholar] [CrossRef]
  35. Strübing, C.; Krapivinsky, G.; Krapivinsky, L.; Clapham, D.E. TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron 2001, 29, 645–655. [Google Scholar] [CrossRef]
  36. Bonaventure, P.; Guo, H.; Tian, B.; Liu, X.; Bittner, A.; Roland, B.; Salunga, R.; Ma, X.J.; Kamme, F.; Meurers, B.; et al. Nuclei and subnuclei gene expression profiling in mammalian brain. Brain Res. 2002, 943, 38–47. [Google Scholar] [CrossRef]
  37. Okada, T.; Inoue, R.; Yamazaki, K.; Maeda, A.; Kurosaki, T.; Yamakuni, T.; Tanaka, I.; Shimizu, S.; Ikenaka, K.; Imoto, K.; et al. Molecular and functional characterization of a novel mouse transient receptor potential protein homologue TRP7. Ca(2+)-permeable cation channel that is constitutively activated and enhanced by stimulation of G protein-coupled receptor. J. Biol. Chem. 1999, 274, 27359–27370. [Google Scholar] [CrossRef]
  38. Flockerzi, V.; Jung, C.; Aberle, T.; Meissner, M.; Freichel, M.; Philipp, S.E.; Nastainczyk, W.; Maurer, P.; Zimmermann, R. Specific detection and semi-quantitative analysis of TRPC4 protein expression by antibodies. Pflugers Arch. 2005, 451, 81–86. [Google Scholar] [CrossRef]
  39. Nagamine, K.; Kudoh, J.; Minoshima, S.; Kawasaki, K.; Asakawa, S.; Ito, F.; Shimizu, N. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics 1998, 54, 124–131. [Google Scholar] [CrossRef]
  40. Hofmann, T.; Schaefer, M.; Schultz, G.; Gudermann, T. Subunit composition of mammalian transient receptor potential channels in living cells. Proc. Natl. Acad. Sci. USA 2002, 99, 7461–7466. [Google Scholar] [CrossRef]
  41. Goel, M.; Sinkins, W.G.; Schilling, W.P. Selective association of TRPC channel subunits in rat brain synaptosomes. J. Biol. Chem. 2002, 277, 48303–48310. [Google Scholar] [CrossRef]
  42. Strübing, C.; Krapivinsky, G.; Krapivinsky, L.; Clapham, D.E. Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J. Biol. Chem. 2003, 278, 39014–39019. [Google Scholar] [CrossRef]
  43. Yuan, J.P.; Zeng, W.; Huang, G.N.; Worley, P.F.; Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat. Cell Biol. 2007, 9, 636–645. [Google Scholar] [CrossRef]
  44. Boulay, G.; Brown, D.M.; Qin, N.; Jiang, M.; Dietrich, A.; Zhu, M.X.; Chen, Z.; Birnbaumer, M.; Mikoshiba, K.; Birnbaumer, L. Modulation of Ca2+ entry by polypeptides of the inositol 1,4,5-trisphosphate receptor (IP3R) that bind transient receptor potential (TRP): Evidence for roles of TRP and IP3R in store depletion-activated Ca2+ entry. Proc. Natl. Acad. Sci. USA 1999, 96, 14955–14960. [Google Scholar] [CrossRef]
  45. Worley, P.F.; Zeng, W.; Huang, G.N.; Yuan, J.P.; Kim, J.Y.; Lee, M.G.; Muallem, S. TRPC channels as STIM1-regulated store-operated channels. Cell Calcium 2007, 42, 205–211. [Google Scholar]
  46. Kim, S.J.; Kim, Y.S.; Yuan, J.P.; Petralia, R.S.; Worley, P.F.; Linden, D.J. Activation of TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature 2003, 426, 285–291. [Google Scholar] [CrossRef]
  47. Stroh, O.; Freichel, M.; Kretz, O.; Birnbaumer, L.; Hartmann, J.; Egger, V. NMDA receptor-dependent synaptic activation of TRPC channels in olfactory bulb granule cells. J. Neurosci. 2012, 32, 5737–5746. [Google Scholar] [CrossRef]
  48. Trebak, M.; Lemonnier, L.; Smyth, J.T.; Vazquez, G.; Putney, J.W., Jr. Phospholipase C-coupled receptors and activation of TRPC channels. Handb. Exp. Pharmacol. 2007, 179, 593–614. [Google Scholar] [CrossRef]
  49. Putney, J. Physiological mechanisms of TRPC activation. Pflugers Arch. 2005, 451, 29–34. [Google Scholar] [CrossRef]
  50. Singh, A.; Hildebrand, M.E.; Garcia, E.; Snutch, T.P. The transient receptor potential channel antagonist SKF96365 is a potent blocker of low-voltage-activated T-type calcium channels. Br. J. Pharm. 2010, 160, 1464–1475. [Google Scholar] [CrossRef]
  51. Jung, S.; Mühle, A.; Schaefer, M.; Strotmann, R.; Schultz, G.; Plant, T.D. Lanthanides potentiate TRPC5 currents by an action at extracellular sites close to the pore mouth. J. Biol. Chem. 2003, 278, 3562–3571. [Google Scholar]
  52. Freichel, M.; Suh, S.H.; Pfeifer, A.; Schweig, U.; Trost, C.; Weissgerber, P.; Biel, M.; Philipp, S.; Freise, D.; Droogmans, G.; et al. Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nat. Cell Biol. 2001, 3, 121–127. [Google Scholar] [CrossRef]
  53. Miller, M.; Shi, J.; Zhu, Y.; Kustov, M.; Tian, J.-B.; Stevens, A.; Wu, M.; Xu, J.; Long, S.; Yang, P.; et al. Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J. Biol. Chem. 2011, 286, 33436–33446. [Google Scholar] [CrossRef]
  54. Tian, J.; Thakur, D.P.; Lu, Y.; Zhu, Y.; Freichel, M.; Flockerzi, V.; Zhu, M.X. Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels. Pflugers Arch. 2013, in press. [Google Scholar]
  55. Kiyonaka, S.; Kato, K.; Nishida, M.; Mio, K.; Numaga, T.; Sawaguchi, Y.; Yoshida, T.; Wakamori, M.; Mori, E.; Numata, T.; et al. Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proc. Nat. Acad. Sci. USA 2009, 106, 5400–5405. [Google Scholar] [CrossRef]
  56. Leuner, K.; Heiser, J.H.; Derksen, S.; Mladenov, M.I.; Fehske, C.J.; Schubert, R.; Gollasch, M.; Schneider, G.; Harteneck, C.; Chatterjee, S.S.; et al. Simple 2,4-Diacylphloroglucinols as classic transient receptor potential-6 activators-Identification of a novel pharmacophore. Mol. Pharmacol. 2010, 77, 368–377. [Google Scholar] [CrossRef]
  57. Urban, N.; Hill, K.; Wang, L.; Kuebler, W.M.; Schaefer, M. Novel pharmacological TRPC inhibitors block hypoxia-induced vasoconstriction. Cell Calcium 2012, 51, 194–206. [Google Scholar] [CrossRef]
  58. Washburn, D.G.; Holt, D.A.; Dodson, J.; McAtee, J.J.; Terrell, L.R.; Barton, L.; Manns, S.; Waszkiewicz, A.; Pritchard, C.; Gillie, D.J.; et al. The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore. Bioorg. Med. Chem. Lett. 2013, 23, 4979–4984. [Google Scholar] [CrossRef]
  59. Ding, Y.; Winters, A.; Ding, M.; Graham, S.; Akopova, I.; Muallem, S.; Wang, Y.; Hong, J.H.; Gryczynski, Z.; Yang, S.-H.; et al. Reactive oxygen species-mediated TRPC6 protein activation in vascular myocytes, a mechanism for vasoconstrictor-regulated vascular tone. J. Biol. Chem. 2011, 286, 31799–31809. [Google Scholar] [CrossRef]
  60. Chen, W.; Oberwinkler, H.; Werner, F.; Gaßner, B.; Nakagawa, H.; Feil, R.; Hofmann, F.; Schlossmann, J.; Dietrich, A.; Gudermann, T.; et al. Atrial natriuretic peptide-mediated inhibition of microcirculatory endothelial Ca2+ and permeability response to histamine involves cGMP-dependent protein kinase I and TRPC6 channels. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 2121–2129. [Google Scholar]
  61. Shwe, U.T.; Phelan, K.D.; Birnbaumer, L.; Zheng, F. The effects of putative TRPC channel blockers on the neuronal TRPC channels with defined molecular identity. (to be submitted).
  62. Gasparini, F.; Kuhn, R.; Pin, J.-P. Allosteric modulators of group I metabotropic glutamate receptors: Novel subtype-selective ligands and therapeutic perspectives. Curr. Opin. Pharmacol. 2002, 2, 43–49. [Google Scholar] [CrossRef]
  63. Bleasdale, J.E.; Thakur, N.R.; Gremban, R.S.; Bundy, G.L.; Fitzpatrick, F.A.; Smith, R.J.; Bunting, S. Selective inhibition of receptor-coupled phospholipase C-dependent processes in human platelets and polymorphonuclear neutrophils. J. Pharmacol. Exp. Ther. 1990, 255, 756–768. [Google Scholar]
  64. Kandel, E.R.; Spencer, W.A. Electrophysiology of hippocampal neurons. II. After-potentials and repetitive firing. J. Neurophysiol. 1961, 24, 243–259. [Google Scholar]
  65. McCormick, D.A.; Contreras, D. On the cellular and network bases of epileptic seizures. Ann. Rev. Physiol. 2001, 63, 815–846. [Google Scholar] [CrossRef]
  66. Azouz, R.; Jensen, M.S.; Yaari, Y. Ionic basis of spike after-depolarization and burst generation in adult rat hippocampal CA1 pyramidal cells. J. Physiol. (Lond.) 1996, 492, 211–223. [Google Scholar]
  67. Hildebrand, M.E.; Isope, P.; Miyazaki, T.; Nakaya, T.; Garcia, E.; Feltz, A.; Schneider, T.; Hescheler, J.; Kano, M.; Sakimura, K.; et al. Functional coupling between mGluR1 and Cav3.1 T-type calcium channels contributes to parallel fiber-induced fast calcium signaling within Purkinje cell dendritic spines. J. Neurosci. 2009, 29, 9668–9682. [Google Scholar] [CrossRef]
  68. Park, J.-Y.; Remy, S.; Varela, J.; Cooper, D.C.; Chung, S.; Kang, H.W.; Lee, J.-H.; Spruston, N. A post-burst afterdepolarization is mediated by Group I metabotropic glutamate receptor-dependent upregulation of Cav2.3 R-Type calcium channels in CA1 Pyramidal Neurons. PLoS Biol. 2010, 8, e1000534. [Google Scholar] [CrossRef]
  69. Wong, R.K.S.; Prince, D.A. Afterpotential generation in hippocampal pyramidal neurons. J. Neurophysiol. 1981, 45, 86–97. [Google Scholar]
  70. Phelan, K.D.; Shwe, U.T.; Abramowitz, J.; Wu, H.; Rhee, S.W.; Howell, M.D.; Gottschall, P.E.; Freichel, M.; Flockerzi, V.; Birnbaumer, L.; et al. Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol. Pharmacol. 2013, 83, 429–438. [Google Scholar] [CrossRef]
  71. Yan, H.D.; Villalobos, C.; Andrade, R. TRPC channels mediate a muscarinic receptor-induced afterdepolarization in cerebral cortex. J. Neurosci. 2009, 29, 10038–10046. [Google Scholar]
  72. Tai, C.; Hines, D.J.; Choi, H.B.; MacVicar, B.A. Plasma membrane insertion of TRPC5 channels contributes to the cholinergic plateau potential in hippocampal CA1 pyramidal neurons. Hippocampus 2011, 21, 958–967. [Google Scholar]
  73. Zhang, Z.; Reboreda, A.; Alonso, A.; Barker, P.A.; Séguéla, P. TRPC channels underlie cholinergic plateau potentials and persistent activity in entorhinal cortex. Hippocampus 2011, 21, 386–397. [Google Scholar] [CrossRef]
  74. Stoop, R.; Conquet, F.; Zuber, B.; Voronin, L.L.; Pralong, E. Activation of metabotropic glutamate 5 and NMDA receptors underlies the induction of persistent bursting and associated long-lasting changes in CA3 recurrent connections. J. Neurosci. 2003, 23, 5634–5644. [Google Scholar]
  75. Bains, J.S.; Longacher, J.M.; Staley, K.J. Reciprocal interactions between CA3 network activity and strength of recurrent collateral synapses. Nat. Neurosci. 1999, 2, 720–726. [Google Scholar] [CrossRef]
  76. He, Z.; Jia, C.; Feng, S.; Zhou, K.; Tai, Y.; Bai, X.; Wang, Y. TRPC5 channel is the mediator of neurotrophin-3 in regulating dendritic growth via CaMKIIα in rat hippocampal neurons. J. Neurosci. 2012, 32, 9383–9395. [Google Scholar] [CrossRef]
  77. Narayanan, K.L.; Irmady, K.; Subramaniam, S.; Unsicker, K.; von Bohlen und Halbach, O. Evidence that TRPC1 is involved in hippocampal glutamate-induced cell death. Neurosci. Lett. 2008, 446, 117–122. [Google Scholar] [CrossRef]
  78. Amaral, M.D.; Pozzo-Miller, L. TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J. Neurosci. 2007, 27, 5179–5189. [Google Scholar] [CrossRef]
  79. Kim, D.S.; Ryu, H.J.; Kim, J.E.; Kang, T.C. The reverse roles of transient receptor potential canonical channel-3 and -6 in neuronal death following pilocarpine-induced status epilepticus. Cell Mol. Neurobiol. 2013, 33, 99–109. [Google Scholar] [CrossRef]
  80. Li, H.; Huang, J.; Du, W.; Jia, C.; Yao, H.; Wang, Y. TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity. J. Neurochem. 2012, 123, 1010–1018. [Google Scholar] [CrossRef]
  81. Lin, Y.; Zhang, J.C.; Fu, J.; Chen, F.; Wang, J.; Wu, Z.L.; Yuan, S.Y. Hyperforin attenuates brain damage induced by transient middle cerebral artery occlusion (MCAO) in rats via inhibition of TRPC6 channels degradation. J. Cereb. Blood Flow Metable 2013, 33, 253–262. [Google Scholar] [CrossRef]

Share and Cite

MDPI and ACS Style

Zheng, F.; Phelan, K.D. The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity. Cells 2014, 3, 288-303. https://doi.org/10.3390/cells3020288

AMA Style

Zheng F, Phelan KD. The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity. Cells. 2014; 3(2):288-303. https://doi.org/10.3390/cells3020288

Chicago/Turabian Style

Zheng, Fang, and Kevin D. Phelan. 2014. "The Role of Canonical Transient Receptor Potential Channels in Seizure and Excitotoxicity" Cells 3, no. 2: 288-303. https://doi.org/10.3390/cells3020288

Article Metrics

Back to TopTop