Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice

Jie, Pinghui; Lu, Zihong; Hong, Zhiwen; Li, Lin; Zhou, Libin; Li, Yingchun; Zhou, Rong; Zhou, Ye-Bo; Du, Yumin; Chen, Lei; Chen, Ling

doi:10.1007/s12035-014-8992-2

Cited by 76 publications

(89 citation statements)

References 37 publications

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“…In our previous studies, chronic activation of TRPV4 may change the expression of voltage-gated sodium channels and glutamate receptors [5, 37]. Here, hippocampal protein levels of GlyR α1, α2, α3 and β subunits were examined in GSK1016790A-injected mice.…”

Section: Resultsmentioning

confidence: 97%

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glycine plays an important role in regulating hippocampal inhibitory/ excitatory neurotransmission through activating glycine receptors (GlyRs) and acting as a co-agonist of N-methyl-d-aspartate-type glutamate receptors. Activation of transient receptor potential vanilloid 4 (TRPV4) is reported to inhibit hippocampal A-type γ-aminobutyric acid receptor, a ligand-gated chloride ion channel. GlyRs are also ligand-gated chloride ion channels and this paper aimed to explore whether activation of TRPV4 could modulate GlyRs. Methods: Whole-cell patch clamp recording was employed to record glycine-activated current (I_Gly) and Western blot was conducted to assess GlyRs subunits protein expression. Results: Application of TRPV4 agonist (GSK1016790A or 5,6-EET) increased I_Gly in mouse hippocampal CA1 pyramidal neurons. This action was blocked by specific antagonists of TRPV4 (RN-1734 or HC-067047) and GlyR (strychnine), indicating that activation of TRPV4 increases strychnine-sensitive GlyR function in mouse hippocampal pyramidal neurons. GSK1016790A-induced increase in I_Gly was significantly attenuated by protein kinase C (PKC) (BIM II or D-sphingosine) or calcium/calmodulin-dependent protein kinase II (CaMKII) (KN-62 or KN-93) antagonists but was unaffected by protein kinase A or protein tyrosine kinase antagonists. Finally, hippocampal protein levels of GlyR α1 α2, α3 and β subunits were not changed by treatment with GSK1016790A for 30 min or 1 h, but GlyR α2, α3 and β subunits protein levels increased in mice that were intracerebroventricularly (icv.) injected with GSK1016790A for 5 d. Conclusion: Activation of TRPV4 increases GlyR function and expression, and PKC and CaMKII signaling pathways are involved in TRPV4 activation-induced increase in I_Gly. This study indicates that GlyRs may be effective targets for TRPV4-induced modulation of hippocampal inhibitory neurotransmission.

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Section: Resultsmentioning

confidence: 97%

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons

Wang

et al. 2018

Cell Physiol Biochem

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“…Previous reports from our group showed that activation of TRPV4 reduced the phosphorylation of Akt (Jie et al, 2015, 2016; Hong et al, 2016). AMPK is a serine/threonine kinase that functions as an important sensor in energy homeostasis in mammalian cells.…”

Section: Discussionmentioning

confidence: 70%

“…GSK1016790A is a synthetic agonist of TRPV4 and has been used to activate TRPV4 both in vivo and in vitro (Vincent and Duncton, 2011; Jie et al, 2015, 2016; Hong et al, 2016). AICAR is a commonly used and specific activator of AMPK, and compound C (CC) is a specific antagonist of AMPK (Han et al, 2005; Venna et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…740 Y-P (or PDGFR 740 Y-P) can bind with high affinity to p85 subunit of PI3K and has been widely used as a special agonist of PI3K (Derossi et al, 1998; Williams and Doherty, 1999). GSK1016790A, AICAR and 740 Y-P were administered by intracerebroventricular (icv) injections as described in previous reports (Han et al, 2005; Jie et al, 2015, 2016). Briefly, these drugs were injected into the right lateral ventricle (0.3 mm posterior, 1.0 mm lateral, and 2.5 mm ventral to the bregma) using a stepper motor-controlled microsyringe (Stoelting, Wood Dale, IL, United States) at a rate of 0.2 μl/min.…”

Section: Methodsmentioning

confidence: 99%

“…CC (10 mg/Kg), AICAR (2 mM/mouse) or 740 Y-P (30 μM/mouse) was injected 30 min before GSK1016790A injection and then injected once daily for 5 days. The concentrations of these drugs were chosen based on previous reports (Han et al, 2005; Li J. et al, 2010; Liu et al, 2012; Venna et al, 2012; Jie et al, 2015, 2016). The final volume was 2 μl for icv and 0.2 ml for ip injection.…”

Section: Methodsmentioning

confidence: 99%

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Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways

Tian

Wang

et al. 2017

Front. Mol. Neurosci.

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Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i). Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG). The present study aimed to examine the effect of TRPV4 activation on the dendrite morphology of newborn neurons in the adult hippocampal DG. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days (GSK1016790A-injected mice) reduced the number of doublecortin immunopositive (DCX+) cells and DCX+ fibers in the hippocampal DG, showing the impaired dendritic arborization of newborn neurons. The phosphorylated AMP-activated protein kinase (p-AMPK) protein level increased from 30 min to 2 h, and then decreased from 1 to 5 days after GSK1016790A injection. The phosphorylated protein kinase B (p-Akt) protein level decreased from 30 min to 5 days after GSK1016790A injection; this decrease was markedly attenuated by the AMPK antagonist compound C (CC), but not by the AMPK agonist AICAR. Moreover, the phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6k) protein levels were decreased by GSK1016790A; these changes were sensitive to 740 Y-P and CC. The phosphorylation of glycogen synthase kinase 3β (GSK3β) at Y216 was increased by GSK1016790A, and this change was accompanied by increased phosphorylation of microtubule-associated protein 2 (MAP2) and collapsin response mediator protein-2 (CRMP-2). These changes were markedly blocked by 740 Y-P and CC. Finally, GSK1016790A-induced decrease of DCX+ cells and DCX+ fibers was markedly attenuated by 740 Y-P and CC, but was unaffected by AICAR. We conclude that TRPV4 activation impairs the dendritic arborization of newborn neurons through increasing AMPK and inhibiting Akt to inhibit the mTOR-p70S6k pathway, activate GSK3β and thereby result in the inhibition of MAP2 and CRMP-2 function.

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TRPV4: A trigger of pathological RhoA activation in neurological disease

2022

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Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton.Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4-RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood-brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4-RhoA activation in a range of neurological diseases.

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Activation of Transient Receptor Potential Vanilloid 4 is Involved in Neuronal Injury in Middle Cerebral Artery Occlusion in Mice

Cited by 76 publications

References 37 publications

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons

Transient Receptor Potential Vanilloid 4 Activation-Induced Increase in Glycine-Activated Current in Mouse Hippocampal Pyramidal Neurons

Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways

TRPV4: A trigger of pathological RhoA activation in neurological disease

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