The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734

Feetham, Claire H.; Nunn, Nicolas; Barrett‐Jolley, Richard

doi:10.3389/fphar.2015.00083

Cited by 14 publications

(27 citation statements)

References 61 publications

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“…In a third study, Kinsman et al found no difference in water intake following hyperosmotic challenge between this latter model and controls. Besides these KO models, other studies linked TRPV4 to AVP secretion in SON [11], modulated thirst with a TRPV4 agonist [41], or showed its role in osmosensitivity of the PVN [13,14]. TRPV4 has also been described as a peripheral osmoreceptor in nerve endings surrounding hepatic blood vessels [19].…”

Section: Discussionmentioning

confidence: 99%

TRPV4 is associated with central rather than nephrogenic osmoregulation

Janas

Seghers

Schakman

et al. 2016

Pflugers Arch - Eur J Physiol

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TRPV4 is a polymodal cation channel expressed in osmosensitive neurons of the hypothalamus and in the mammalian nephron. The segmental distribution and role(s) of TRPV4 in osmoregulation remain debated. We investigated the renal distribution pattern of TRPV4 and the functional consequences of its disruption in mouse models. Using qPCR on microdissected segments, immunohistochemistry, and a LacZ reporter mouse, we found that TRPV4 is abundantly expressed in the proximal tubule, the late distal convoluted tubule, and throughout the connecting tubule and collecting duct, including principal and intercalated cells. TRPV4 was undetectable in the glomeruli and thick ascending limb and weakly abundant in the early distal convoluted tubule. Metabolic studies in Trpv4 +/+ and Trpv4 −/− littermates revealed that the lack of TRPV4 did not influence activity, food and water intake, renal function, and urinary concentration at baseline. The mice showed a similar response to furosemide, water loading and deprivation, acid loading, and dietary NaCl restriction. However, Trpv4 −/− mice showed a significantly lower vasopressin synthesis and release after water deprivation, with a loss of the positive correlation between plasma osmolality and plasma vasopressin levels, and a delayed water intake upon acute administration of hypertonic saline. Specific activation of TRPV4 in primary cultures of proximal tubule cells increased albumin uptake, whereas no effect of TRPV4 deletion could be observed at baseline. These data reveal that, despite its abundant expression in tubular segments, TRPV4 does not play a major Philippe Gailly and Olivier Devuyst co-directed the study and are cosenior authors.Sylvie Janas and François Seghers contributed equally to this work.Electronic supplementary material The online version of this article

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Section: Discussionmentioning

confidence: 99%

TRPV4 is associated with central rather than nephrogenic osmoregulation

Janas

Seghers

Schakman

et al. 2016

Pflugers Arch - Eur J Physiol

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“…Neuronal TRPV4 channels may therefore be an important therapeutic target for cognitive, motor and ageing-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 and 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 2012Shigetomi et al , 2013Wei et al 2016). Such inhibitors, if 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).…”

Section: Role Of Trpv4 In Cns Neuronsmentioning

confidence: 99%

“…; Morty & Kuebler, ; Feetham et al . ; Qi et al . ) and also as ‘dual inhibitors’ of TRPV4 and TRPA1 (Kanju et al .…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic function of TRPV4 ion channels in the central nervous system

Kanju

Liedtke

2016

Experimental Physiology

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TRPV4 ion channels are osmo-mechano-TRP channels with pleiotropic function and expression in many different types of tissues and cells. They have also been found involved in pain and inflammation. Studies have focused on the role of TRPV4 in peripheral sensory neurons, but its expression and function in central nervous glial cells and neurons has also been documented. In this overview, based on the senior author’s lecture at the recent physiology meeting in Dublin, we concisely review evidence of TRPV4 expression and function in the CNS, and how TRPV4 function can be modulated for therapeutic benefit of neuro-psychiatric disorders. Novel TRPV4-inhibitory compounds developed recently in the authors’ lab will also be discussed

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“…Similarly, an in vivo study investigated whether hypotonic TRPV4 driven neuronal inhibition modulated cardiovascular parameters. In mice, intracerebroventricular administration of hypotonic solutions decreased mean blood pressure but not heart rate and inhibition of the TRPV4 channels abolished these effects (Feetham, Nunn & Barrett‐Jolley, ). These studies support a central TRPV4 channel as important for sensing osmolality and the authors proposed the effects of its activation to be mediated by the channel expressed on spinally projecting preautonomic neurons (Feetham, Nunn, Lewis, Dart, & Barrett‐Jolley, ).…”

Section: Discussionmentioning

confidence: 99%

“…Functionally, TRPV4 and calcium activated potassium (K Ca ) ion channels have been shown to couple as osmosensors in the PVN in mouse brain slices and rat isolated PVN neurons (Feetham, Nunn, Lewis, Dart, & Barrett‐Jolley, ). Again in mice, intracerebroventricular administration of hypotonic artificial cerebrospinal fluid decreases blood pressure but not heart rate and inhibition of the TRPV4 ion channel attenuated this effect (Feetham, Nunn, & Barrett‐Jolley, ). While these studies demonstrate a functional role for TRPV4 in osmosensing within the PVN, they do not establish which neurons express the channel, leaving open the question of the neuronal mechanism underlying these observations.…”

Section: Introductionmentioning

confidence: 99%

Transient receptor potential vanilloid type 4 is expressed in vasopressinergic neurons within the magnocellular subdivision of the rat paraventricular nucleus of the hypothalamus

Shenton

Pyner

2018

J of Comparative Neurology

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Changes in plasma osmolality can drive changes in the output from brain centres known to control cardiovascular homeostasis, such as the paraventricular nucleus of the hypothalamus (PVN). Within the PVN hypotonicity reduces the firing rate of parvocellular neurons, a neuronal pool known to be involved in modulating sympathetic vasomotor tone. Also present in the PVN is the transient receptor potential vanilloid type 4 (TRPV4) ion channel. Activation of TRPV4 within the PVN mimics the reduction in firing rate of the parvocellular neurons but it is unknown if these neurons express the channel. We used neuronal tracing and immunohistochemistry to investigate which neurons expressed the TRPV4 ion channel protein and its relationship with neurons known to play a role in plasma volume regulation. Spinally projecting preautonomic neurons within the PVN were labelled after spinal cord injection of FluoroGold (FG). This was followed by immunolabelling with anti-TRPV4 antibody in combination with either anti-oxytocin (OXT) or anti-vasopressin (AVP). The TRPV4 ion channel was expressed on 63% of the vasopressinergic magnocellular neurosecretory cells found predominantly within the posterior magnocellular division of the PVN. Oxytocinergic neurons and FG labelled preautonomic neurons were present in the same location, but were distinct from the TRPV4/vasopressin expressing neurons. Vasopressinergic neurons within the supraoptic nucleus (SON) were also found to express TRPV4 and the fibres extending between the SON and PVN. In conclusion within the PVN, TRPV4 is well placed to respond to changes in osmolality by regulating vasopressin secretion, which in turn influences sympathetic output via preautonomic neurons.

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The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734

Cited by 14 publications

References 61 publications

TRPV4 is associated with central rather than nephrogenic osmoregulation

TRPV4 is associated with central rather than nephrogenic osmoregulation

Pleiotropic function of TRPV4 ion channels in the central nervous system

Transient receptor potential vanilloid type 4 is expressed in vasopressinergic neurons within the magnocellular subdivision of the rat paraventricular nucleus of the hypothalamus

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