Influence of the calcium voltage-gated channel auxiliary subunit (CACNA2D1) absence on intraocular pressure in mice

Exp Eye Res. 2024 Apr:241:109835. doi: 10.1016/j.exer.2024.109835. Epub 2024 Feb 17.

Abstract

The etiology of elevated intraocular pressure (IOP), a major risk factor for glaucoma (optic nerve atrophy), is poorly understood despite continued efforts. Although the gene variant of CACNA2D1 (encoding α2δ1), a calcium voltage-gated channel auxiliary subunit, has been reported to be associated with primary open-angle glaucoma, and the pharmacological mitigation of α2δ1 activity by pregabalin lowers IOP, the cellular basis for α2δ1 role in the modulation of IOP remains unclear. Our recent findings reveled readily detectable levels of α2δ1 and its ligand thrombospondin in the cytoskeletome fraction of human trabecular meshwork (TM) cells. To understand the direct role of α2δ1 in the modulation of IOP, we evaluated α2δ1 null mice for changes in IOP and found a moderate (∼10%) but significant decrease in IOP compared to littermate wild type control mice. Additionally, to gain cellular insights into α2δ1 antagonist (pregabalin) induced IOP changes, we assessed pregabalin's effects on human TM cell actin cytoskeletal organization and cell adhesive interactions in comparison with a Rho kinase inhibitor (Y27632), a known ocular hypotensive agent. Unlike Y27632, pregabalin did not have overt effects on cell morphology, actin cytoskeletal organization, or cell adhesion in human TM cells. These results reveal a modest but significant decrease in IOP in α2δ1 deficient mice, and this response appears to be not associated with the contractile and cell adhesive characteristics of TM cells based on the findings of pregabalin effects on isolated TM cells. Therefore, the mechanism by which pregabalin lowers IOP remains elusive.

Keywords: CACNA2D1; Cytoskeleton; Ocular hypertension; Pregabalin; Trabecular meshwork.

MeSH terms

  • Actins / metabolism
  • Amides*
  • Animals
  • Calcium / metabolism
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Glaucoma* / metabolism
  • Glaucoma, Open-Angle* / genetics
  • Glaucoma, Open-Angle* / metabolism
  • Humans
  • Intraocular Pressure
  • Mice
  • Pregabalin
  • Pyridines*
  • Trabecular Meshwork / metabolism

Substances

  • Actins
  • Amides
  • CACNA2D1 protein, human
  • Calcium
  • Calcium Channels
  • Pregabalin
  • Pyridines
  • Y 27632
  • CACNA2D1 protein, mouse