Cholesterol regulates polymodal sensory transduction in Müller glia

Abstract

Over- and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Müller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supplementation of cholesterol using the methyl-beta cyclodextrin (MβCD) delivery vehicle. Cholesterol extraction disrupted lipid rafts and caveolae without affecting TRPV4 trafficking or membrane localization protein. However, MβCD suppressed agonist (GSK1016790A)- and temperature-evoked elevations in [Ca²⁺]_i, and suppressed transcellular propagation of Ca²⁺ waves. Lowering the free membrane cholesterol content markedly prolonged the time-course of the glial swelling response, whereas MβCD:cholesterol supplementation enhanced agonist- and temperature-induced Ca²⁺ signals and shortened the swelling response. Taken together, these data show that membrane cholesterol modulates polymodal transduction of agonists, swelling and temperature stimuli in retinal radial glia and suggest that dyslipidemic retinas might be associated with abnormal glial transduction of ambient sensory inputs.

Main Points

• Extraction and supplementation of free membrane cholesterol regulate calcium homeostasis in retinal Müller cells
• Cholesterol differentially regulates polymodal TRPV4 activation by chemical agonists, swelling and temperature
• TRPV4 trafficking and expression are independent of lipid rafts

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vD9S7t
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