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

Cholesterol regulates polymodal sensory transduction in Müller glia

“…Saturable cholesterol recognition sites such as CRAC/CARC might confer sensitivity to chemical agents, temperature or membrane stretch by interacting with protein domains that transduce these stimulus modalities (Vriens et al, ), as indicated by the additivity of different stimuli when they are applied at suboptimal levels (Toft‐Bertelsen et al, ). While it is unclear why cholesterol extraction fails to suppress the amplitude of swelling‐induced TRPV4 signals, it is possible that AQP4 channels and phospholipase A2 which drive the rate of swelling and TRPV4 activation in Müller cells (Iuso & Krizaj, ) are relatively independent of membrane cholesterol whereas the extended time course of HTS‐evoked calcium signals in the presence of MβCD may involve decreased Ca 2+ ‐dependent channel inactivation and/or regulatory volume decrease (RVD) (Levitan & Barrantes, ). Of note, TRPV4 expressed in yeast (which cannot synthesize cholesterol) continues to be activated by changes in osmolarity, even as temperature sensitivity (which may require cholesterol) is lost (Loukin, Su, & Kung, ).…”

Turning down the volume: Astrocyte volume change in the generation and termination of epileptic seizures

“…Emerging evidence suggests that astrocyte swelling itself may provide the stimulus necessary for RVD to occur. In Müller glia (an “astrocyte-like” glial cell type in the retina), rapid water influx through AQP4 produces membrane stretch, which then activates nearby stretch-activated TRPV4 channels to permit Ca 2+ entry to promote RVD (Iuso and Krizaj 2016; Jo et al 2015). While the requirement of TRPV4 opening and Ca 2+ influx in astrocytic RVD has recently been questioned (Mola et al 2016), these findings suggest that rapid water influx is an important trigger for subsequent astrocyte volume regulation (Benfenati et al 2011; Mola et al 2016).…”

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

“…We know that Ca 2C waves in M€ uller cells can be evoked by numerous stimuli that include light, mechanical stress and hypotonicity 14,17,18 and that wave propagation can involve intrinsic P 2 receptors, ryanodine receptors, glutamate receptors and TRPV4 channels 12,16,18 possibly in association with AQP4. 20 As in cortical astrocytes, the fundamental step leading to regenerative Ca 2C events is likely to involve regenerative activation of the ER Ca 2C pool via the activation of GPCRs, phospholipase C and production of IP 3 ; whereas it remains to be seen whether mammalian M€ uller cells use ryanodine receptor signaling in wave propagation. 13,31 Early studies showed that Ca 2C signals between adjacent M€ uller glia and astrocytes, and retinal neurons and glia, spread through gap junctions and/or diffusion of extracellular molecules such as ATP.…”

“…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.…”