Swelling and Eicosanoid Metabolites Differentially Gate TRPV4 Channels in Retinal Neurons and Glia

Abstract

Activity-dependent shifts in ionic concentrations

Optogenetic activation of mechanically insensitive afferents in mouse colorectum reveals chemosensitivity

“…Rather than encoding hyperosmotic challenge, most channels are activated by hypotonic stimuli and presumed cell swelling, including TrpV4 that is widely expressed in visceral sensory neurons (6,22,32). In contrast, hypertonic stimuli cause hyperpolarization in some cells (16,33) and presumably result in cell membrane shrinkage, contributing to an increased activation threshold for stretch-activated ion channels, consistent with a previous finding that AHS significantly reduced colorectal afferent response frequency and increased response threshold to mechanical stretch (21).…”

TRPV4-AQP4 interactions ‘turbocharge’ astroglial sensitivity to small osmotic gradients

“…2 Sustained over time, this may result in reactive gliosis and inflammation. 5 A similar conclusion was concurrently reached for cortical astroglia. 7 The study also addressed the potential contribution of TRPV4-AQP4 interactions to regulatory volume decrease (RVD), a key process that protects cells against pathological swelling.…”

“…2 TRPV4 ¡/¡ and AQP4 ¡/¡ retinas did not exhibit a phenotype in terms of morphology, protein trafficking or transcription of housekeeping genes whereas TRPV4-deficient retinas showed mild levels of reactive gliosis, consistent with the importance of the channel in glial steady-state function. 4,5 Interestingly, elimination of TRPV4 was associated with reduced mRNA levels of Aqp4 and Kcnj10 (which encodes the Kir4.1 inward-rectifying K C channel) whereas AQP4 ¡/¡ retinas showed suppressed Kcnj10 transcription. The interdependence of 3 highly dissimilar osmo-relevant channels at the molecular level might reflect clustering with the M€ uller transcriptome or linkage through activity-and/or TRPV4-dependent Ca 2C entry.…”

“…In contrast, TRPV4 activation (by agonists or swelling) itself augmented glial swelling through an unknown mechanism that required an increase in [Ca 2C ] i and, possibly, activation of phospholipase A2. 2,4,5 We hypothesize that coordination of activitydependent ionic/water fluxes at the blood-retina barrier critically depends on functional interactions between endfoot TRPV4, AQP4 and Kir4.1 channels. This osmoregulatory complex links changes in glial water permeability, K C uptake, ATP release and Ca 2C homeostasis that occur in response to during neuronal firing, 1,8 to downstream modulation of Aqp4 and Kcnj10 and astroglial function by maintaining the steady-state 'osmo-tensile' homeostasis.…”

Subcellular propagation of calcium waves in Müller glia does not require autocrine/paracrine purinergic signaling

“…Another intriguing feature of store depletion was the transcellular propagation of Ca 2C reminiscent of wave-like phenomena evoked by light, glutamate spillover, mechanical activation, osmotic swelling, activation of TRPV4 channels and ryanodine release channels, and spontaneous waves observed in M€ uller glia in the absence of stimuli. [13][14][15][16][17][18][19][20] Although the physiological significance of transcellular Ca 2C waves in radial glia is not known, it is tempting to speculate that they represent a possible conduit for channeling information from the blood-retina barrier (M€ uller endfeet) and the outer retina (the apical process) to the transcriptional apparatus in the M€ uller cell body. The mechanisms supporting Ca 2C wave propagation were suggested to involve intracellular release channels 13 light-, mechanically-and/or osmotically-induced release of ATP from neurons, 15,21 and autocrine activation of metabotropic receptors.…”