TRPV4 and TRPC1 channels mediate the response to tensile strain in mouse Müller cells

Cell Calcium. 2022 Jun:104:102588. doi: 10.1016/j.ceca.2022.102588. Epub 2022 Apr 5.

Abstract

Müller glia, a pillar of metabolic, volume regulatory and immune/inflammatory signaling in the mammalian retina, are among the earliest responders to mechanical stressors in the eye. Ocular trauma, edema, detachment and glaucoma evoke early inflammatory activation of Müller cells yet the identity of their mechanotransducers and signaling mechanisms downstream remains unknown. Here, we investigate expression of genes that encode putative stretch-activated calcium channels (SACs) in mouse Müller cells and study their responses to dynamical tensile loading in cells loaded with a calcium indicator dye. Transcript levels in purified glia were Trpc1>Piezo1>Trpv2>Trpv4>>Trpv1>Trpa1. Cyclic radial deformation of matrix-coated substrates produced dose-dependent increases in [Ca2+]i that were suppressed by the TRPV4 channel antagonist HC-067047 and by ablation of the Trpv4 gene. Stretch-evoked calcium responses were also reduced by knockdown and pharmacological inhibition of TRPC1 channels whereas the TRPV2 inhibitor tranilast had no effect. These data demonstrate that Müller cells are intrinsically mechanosensitive, with the response to tensile loading mediated through synergistic activation of TRPV4 and TRPC1 channels. Coupling between mechanical stress and Müller Ca2+ homeostasis has treatment implications, since many neuronal injury paradigms in the retina involve calcium dysregulation associated with inflammatory and immune signaling.

Keywords: Calcium; Glaucoma; Glia; Mechanosensitivity; Stretch-activated channels.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling
  • Ependymoglial Cells* / metabolism
  • Ion Channels / metabolism
  • Mammals / metabolism
  • Mice
  • TRPC Cation Channels / metabolism*
  • TRPV Cation Channels* / metabolism

Substances

  • Calcium Channels
  • Ion Channels
  • Piezo1 protein, mouse
  • TRPC Cation Channels
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • transient receptor potential cation channel, subfamily C, member 1
  • Calcium