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

Abstract

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.

The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels

“…GSK1016790A is the potent and selective agonist of TRPV4 that has been widely used as a valuable tool to study the physiological properties of TRPV4 (Pankey et al, 2014; Xu et al, 2016; Tian et al, 2017). Activation of TRPV4 with GSK1016790A has been reported to inhibit TNF-α-induced monocyte adhesion to human endothelial cells, and oral administration of GSK1016790A reduces atherosclerotic plaque formation (Sullivan et al, 2012).…”

TRPV4 Inhibition Improved Myelination and Reduced Glia Reactivity and Inflammation in a Cuprizone-Induced Mouse Model of Demyelination

“…TRPV4 channels mediate Ca 2+ influx into astrocytes and neurons and glutamate accumulation during acute stroke, and knockout of Trpv4 attenuates neuronal calcium elevation (Rakers et al, 2017 ). TRPV4 activation impairs the dendritic branching of hippocampal newborn neurons (Tian et al, 2017 ). Blocking Ca 2+ influx through TRPV4 channels with the TRPV4 inhibitor HC067047 reduces the death of cultured dorsal root ganglion neurons and alleviates paclitaxel-induced neuropathy (Boehmerle et al, 2018 ).…”

Ketamine administration ameliorates anesthesia and surgery‑induced cognitive dysfunction via activation of TRPV4 channel opening

“…The protective effects induced by TRPV4 channel opening have been associated with phosphorylation of AMPK and inhibition of the NF-κB signaling pathway ( 34 , 35 ). In the present study, the effect of surgery on individual proteins in the AMPK/NF-κB signaling pathway was determined using western blotting with pathway-specific antibodies.…”