Pleiotropic function of TRPV4 ion channels in the central nervous system

Introduction

Transient receptor potential, vanilloid type 4 (TRPV4) ion channels (Liedtke et al., 2000) are also expressed in cells of the central nervous system (CNS) including neurons, astrocytes and microglia (White et al., 2016). Cell-physiologic experiments indicate that TRPV4 channels can function as Ca²⁺-permeable cation channels that are gated by various stimuli such as cell swelling, low pH, mechanical stress and temperature (Liedtke & Kim, 2005; Liedtke, 2008; Guilak et al., 2010; McNulty et al., 2015; White et al., 2016). Whether this currently established functional profile is particularly relevant for the role that TRPV4 plays in the CNS remains to be determined. As of today, 16 years after its initial description (Liedtke et al., 2000; Strotmann et al., 2000), studies on specific functions of TRPV4 in various regions of the CNS are not further advanced than the early stages of exploration. Slow progress could be due to low levels of TRPV4 expression in certain cell types within the CNS, yet still contributing to important function. TRPV4 could function both developmentally as well as post-developmentally as a sensor-signaling molecule. Despite this lack of a clear picture, TRPV4 appears to function in glial cells and neurons in basic physiology as well as under specific pathologic conditions, which will be concisely reviewed here. One particular focus of this article will be to relate known findings on TRPV4 in the CNS to what this possibly means for medicinal-translational purposes.

Role of TRPV4 in astrocytes

TRPV4 channels have been found to be expressed in astrocytes. These channels were localized in the plasma membrane of astrocytes and exhibited activation in response to selective agonist showing a typical outwardly rectifying cation current (Benfenati et al., 2007). As a Ca²⁺ permeable channel, TRPV4 was shown to influence neurovascular coupling through Ca²⁺-induced Ca²⁺ release from inositol trisphosphate receptors (IP3Rs) in astrocytic endfeet (Fig. 1A) (Dunn et al., 2013). Studies indicate that astroglial cells can modulate neuronal excitability in hippocampus, cortex and hypothalamus and that TRPV4 might function as a key player in this excitation (Simard & Nedergaard, 2004; Shibasaki et al., 2014). In hippocampus, for example, TRPV4 is highly expressed in astrocytes of the CA1 region and its enhanced expression in this region coincides with the development of astrogliosis (Shirakawa et al., 2010; Butenko et al., 2012).

Other studies suggest that TRPV4 may form a complex with aquaporin-4 (AQP4/TRPV4) and function in control of cell-volume in astrocytes and be involved in regulating interstitial tonicity in the brain, also in formation of brain edema (Benfenati et al., 2011). Furthermore TRPV4 in hippocampal astrocytes were considered to function in oxidative stress-induced cell damage (Bai & Lipski, 2010). Other evidence suggests that astrocytic TRPV4 may be involved in neuronal toxicity evoked by the Alzheimer’s Disease associated peptide, Aß40 (Fig. 1C) (Bai & Lipski, 2014). Astrocytes may therefore play crucial roles in the homeostatic regulation of the CNS not only in physiological but also pathological conditions. TRPV4 channels expressed in astro-glial cells were also shown to mediate infrasound-induced neuronal injury (Fig 1B), a model for blast-induced traumatic brain injury, impairing learning and memory in rats (Shi et al., 2013). This latter study also indicated that injury was more pronounced in the hippocampal CA1 region where astrocytic and microglial activation were observed prior to neuronal apoptosis. Inhibition of TRPV4 protected neurons from infrasound injury by decreasing the expression levels of glial cell-released pro-inflammatory cytokines Il-1β and TNF-α.

Role of TRPV4 in microglia

Interestingly, microglial activation after an injection of lipopolysaccharide (LPS) into the mouse cerebral ventricle was inhibited by concurrent administration of a TRPV4 agonist, 4α-phorbol 12, 13-didecanoate (4α-PDD) (Shirakawa et al., 2010; Konno et al., 2012). Refs (Shirakawa et al., 2010; Konno et al., 2012; Shi et al., 2013) describe seemingly opposing roles of TRPV4 in microglial activation in response to mechanical stimulation vs. chemical stimulation via LPS, indicating the important but complex role of TRPV4 in microglia which is currently under-explored, thus in need of future study.

Role of TRPV4 in CNS neurons

In hippocampal neurons the influx of cations through TRPV4 at physiological temperature may control neuronal excitability by regulating the resting membrane potential (Shibasaki et al., 2007; Shibasaki et al., 2015a) (see also (Shibasaki et al., 2015b)), possibly also in other neurons with wide implications on brain functioning, manifested in several abnormal behavioral parameters in Trpv4^−/− mice, as recently documented (Shibasaki et al., 2015a). Possibly, TRPV4 expression and function in neurons may play a significant role in seizures. For example in larval zebrafish, febrile seizure-related neural activity, which was triggered by a rise in brain temperature was shown to be blocked by TRPV4 antagonist and not GABA re-uptake inhibitors (Hunt et al., 2012). Furthermore, increased TRPV4 expression in cortical lesions of patients with Focal Cortical Dysplasia (FCD), a known form of therapy-refractory epilepsy, indicate that TRPV4 may contribute to cortical malformation and maldevelopment which may facilitate epileptogenesis (Chen et al., 2016). As an important qualifier, bespeaking of the superficial level of inquiry in this field, changed expression levels do not conclusively substantiate any association with disease pathogenesis. In other studies, mutations in TRPV4, hereditary TRPV4 channelopathies, were shown to cause excessive Ca²⁺ influx related to motor nerve axonopathy and spinal muscular atrophy (Fecto et al., 2011; Jang et al., 2012). Although the human genetics of these disorders are clear, it is unclear why some TRPV4 channelopathy mutations cause skeletal malformations, whereas other mutations detrimentally affect spinal motoneurons. For the former, mechanistic evidence as to a feasible patho-mechanism has been provided, at least an initial inroad (Leddy et al., 2014a; Leddy et al., 2014b). In contrast, for the sequence of events between excess Ca²⁺ influx and subsequent moto-neuron dysfunction, this has hitherto remained elusive.

Interestingly in aging, age related expression changes of TRPV4 have been reported in pyramidal cortical neurons, thalamus, basal nuclei of the cerebellum and in the spinal cord (Lee & Choe, 2014). The expression of TRPV4 in neurons in these brain regions could be the basis for (mal-) function of TRPV4 in pathologic conditions. For example, findings by Lee et al [21] on age-dependent expression of TRPV4 channels may be indicative of TRPV4’s role in pathogenesis of age-related neurodegenerative diseases. Neuronal TRPV4 channels may therefore be an important therapeutic target for cognitive, motor and aging-related disorders. TRPV4 inhibitors have been described and were recently described as orally-available compounds (Jia et al., 2004; Krause et al., 2005; Phan et al., 2009; Vincent et al., 2009; Morty & Kuebler, 2014; Feetham et al., 2015; Qi et al., 2015), and also as “dual-inhibitors” of TRPV4/TRPA1 (Kanju et al., 2016), which might be an attractive possibility given the postulated function of astrocytic TRPA1 (Lee et al., 2012; Shigetomi et al., 2012; Shigetomi et al., 2013; Wei et al., 2016). Such inhibitors, in case they are intended for oral use will have to pass through the blood-brain-barrier (although for example the blood-brain-barrier is more penetrable in certain CNS disorders such as multiple sclerosis). As an alternative, in case TRPV4 or TRPV4/TRPA1 (dual-)blockers can potently treat more severe neuropsychiatric illnesses safely and effectively, intra-thecal administration remains a plausible alternative (e.g. therapy-refractory high-intensity chronic pain, note its treatment with intra-thecal ziconotide (McDowell & Pope, 2016)).

Although an interesting topic, the role of TRPV4 in the CNS in systemic osmo- and hydro-mineral regulation is not reviewed here (but see e.g. ref. (Liedtke & Friedman, 2003; Janas et al., 2016)), mainly because it was covered in a separate presentation at the recent joint meeting of APS/The Physiological Society in Dublin, Ireland, and therefore not covered in the overview-talk by the senior author. This qualifier also applies to the important topic of the role of TRPV4 in the CNS in the choroid plexus (Takayama et al., 2014), first described in (Liedtke et al., 2000).

Conclusion

In the current concise review we highlight the important, yet currently under-explored role of TRPV4 in the CNS in glial cells and neurons which has so far not been met with appropriate attention and matching investigative scrutiny.