June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Pregabalin, an IOP-reducing CACNA2D1 antagonist, may also preserve optic nerve health by binding to CACNA2D2.
Author Affiliations & Notes
  • Minjae James Kim
    The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • TJ Hollingsworth
    The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Will Edwards
    The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Monica M Jablonski
    The University of Tennessee Health Science Center, Memphis, Tennessee, United States
  • Footnotes
    Commercial Relationships   Minjae Kim None; TJ Hollingsworth None; Will Edwards None; Monica Jablonski None
  • Footnotes
    Support  NIH Grants R24 EY029950, R43 EY032310, and Research to Prevent Blindness Challenge Grant
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1607 – A0430. doi:
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      Minjae James Kim, TJ Hollingsworth, Will Edwards, Monica M Jablonski; Pregabalin, an IOP-reducing CACNA2D1 antagonist, may also preserve optic nerve health by binding to CACNA2D2.. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1607 – A0430.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : CACNA2D1 is an L-type calcium channel subunit that is expressed by several structures in the eye. Previously, we showed that a topically applied CACNA2D1 antagonist—pregabalin (PRG)—lowered IOP in mice, and that the amplitude of response varied between mice carrying the B and D haplotypes of the gene, originating from C57BL/6 mice (B6) and DBA/2J (D2) mice, respectively. In this study, we aim to show that CACNA2D2, an isoform of CACNA2D1, is expressed in the eye and may be targeted using PRG to modulate optic nerve health.

Methods : Whole eyes from B6 and D2 mice at 1 month of age were immunostained and imaged for CACNA2D1 and CACNA2D2. Systems genetics methods were used to analyze the relationship between optic nerve health and the haplotype of Cacna2d2 using estimates of the number of live axons per optic nerve across the BXD family of mice. Because there is no published crystal structure of CACNA2D2, we used the human N-type voltage gated calcium channel (PDB:7VFU) for homology modeling of both B and D haplotypes of CACNA2D2 (sequence identity: 56%). Molecular docking was performed using Prime software (Schrödinger, Inc., USA).

Results : Immunohistochemical analysis revealed that both CACNA2D1 and CACNA2D2 are expressed in the eye, with CACNA2D2 having its highest expression in the optic nerve. Systems genetics analyses demonstrated a significant reduction in number of live axons per optic nerve in mice with the D haplotype, compared to those with the B haplotype. Finally, molecular docking of PRG to the B haplotype of CACNA2D2 revealed a binding site with a docking score of –10.820 kcal/mol, while that of the D haplotype yielded –5.794 kcal/mol.

Conclusions : Through this study, we confirmed the expression of CACNA2D2 in mouse eyes and using systems genetics analyses demonstrated that it may play a role in modulating optic nerve health. Furthermore, molecular docking of CACNA2D2 revealed PRG’s potential binding site and affinity, which differed between the B and D haplotypes. Together, our findings offer promising evidence to support the exploration of PRG being used therapeutically to not only lower IOP, but also to preserve healthy axons in the eye.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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