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

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 alpha 2 delta 1), a calcium voltage-gated channel auxiliary subunit, has been reported to be associated with primary open-angle glaucoma, and the pharmacological mitigation of alpha 2 delta 1 activity by pregabalin lowers IOP, the cellular basis for alpha 2 delta 1 role in the modulation of IOP remains unclear. Our recent findings reveled readily detectable levels of alpha 2 delta 1 and its ligand thrombospondin in the cytoskeletome fraction of human trabecular meshwork (TM) cells. To understand the direct role of alpha 2 delta 1 in the modulation of IOP, we evaluated alpha 2 delta 1 null mice for changes in IOP and found a moderate (similar to 10%) but significant decrease in IOP compared to littermate wild type control mice. Additionally, to gain cellular insights into alpha 2 delta 1 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 alpha 2 delta 1 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.