Glial cell-expressed mechanosensitive channel TRPV4 mediates infrasound-induced neuronal impairment

Abstract

Vibroacoustic disease, a progressive and systemic disease, mainly involving the central nervous system, is caused by excessive exposure to low-frequency but high-intensity noise generated by various heavy transportations and machineries. Infrasound is a type of low-frequency noise. Our previous studies demonstrated that infrasound at a certain intensity caused neuronal injury in rats but the underlying mechanism(s) is still largely unknown. Here, we showed that glial cell-expressed TRPV4, a Ca(2+)-permeable mechanosensitive channel, mediated infrasound-induced neuronal injury. Among different frequencies and intensities, infrasound at 16 Hz and 130 dB impaired rat learning and memory abilities most severely after 7-14 days exposure, a time during which a prominent loss of hippocampal CA1 neurons was evident. Infrasound also induced significant astrocytic and microglial activation in hippocampal regions following 1- to 7-day exposure, prior to neuronal apoptosis. Moreover, pharmacological inhibition of glial activation in vivo protected against neuronal apoptosis. In vitro, activated glial cell-released proinflammatory cytokines IL-1β and TNF-α were found to be key factors for this neuronal apoptosis. Importantly, infrasound induced an increase in the expression level of TRPV4 both in vivo and in vitro. Knockdown of TRPV4 expression by siRNA or pharmacological inhibition of TRPV4 in cultured glial cells decreased the levels of IL-1β and TNF-α, attenuated neuronal apoptosis, and reduced TRPV4-mediated Ca(2+) influx and NF-κB nuclear translocation. Finally, using various antagonists we revealed that calmodulin and protein kinase C signaling pathways were involved in TRPV4-triggered NF-κB activation. Thus, our results provide the first evidence that glial cell-expressed TRPV4 is a potential key factor responsible for infrasound-induced neuronal impairment.

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

“…Moreover, TRPV4-mediated Ca 2+ entry is supposedly a key factor responsible for infrasound-induced glial activation and subsequent neuronal cell death [32]. In the present study, we firstly reported an over-activation of TRPV4-induced neuronal death in cerebral ischemic injury in vivo.…”

A Novel Subtype of Astrocytes Expressing TRPV4 (Transient Receptor Potential Vanilloid 4) Regulates Neuronal Excitability via Release of Gliotransmitters

“…We and others have previously reported that TRPV4 is an important regulator of neuronal excitability in hippocampal neurons and that TRPV4 is expressed in both astrocytes and neurons (19,24,28,29). Therefore, we sought to determine which types of astrocytes express TRPV4 by combining in situ hybridization and immunohistochemistry in adult mouse hippocampus.…”

“…Thus, TRPV4 ϩ astrocytes might synchronize neuronal excitability and help increase the diversity of synaptic information and brain function. Very recently, the pathophysiological function of TRPV4 in astrocytes has been reported (25,26,28). According to these reports, TRPV4 signaling in astrocytes prevents the progression of brain damage, but the physiological importance of astrocytic TRPV4 under normal conditions has remained ϩ astrocytes, shown by the blue color, are specifically localized in the brain; activation of TRPV4 in these astrocytes causes excitation in neighboring astrocytes through gap junctions and ATP release, shown as red arrows.…”

Ca2+ influx mediates the TRPV4–NO pathway in neuropathic hyperalgesia following chronic compression of the dorsal root ganglion

“…TRPV4 seems to be tightly regulated by intracellular and extracellular Ca 2+ concentrations [17]. Recent study revealed that TRPV4 activation induces Ca 2+ entry and activates Ca 2+ -dependent calmodulin and PKC signaling pathways, resulting in NF-B nuclear translocation and activation; NF-B activation promotes the expression of proinflammatory cytokines IL-1␤ and TNF-␣; excessive release of IL-1␤ and TNF-␣ from glial cells causes damage to neighbouring neurons, ultimately leading to neuronal injury in rats [10]. Thus, it was hypothesized that Ca 2+ influx might be involved in the TRPV4-NO pathway through up-regulating NF-B activity in the CCD model.…”