Role of N-type voltage-dependent calcium channels in autoimmune optic neuritis

Ivana Gadjanski, Susann Boretius, Sarah K. Williams, Paul Lingor, Johanna Knöferle, Muriel B. Sättler, Richard Fairless, Sonja Hochmeister, Kurt Wolfram Sühs, Thomas Michaelis, Jens Frahm, Maria K. Storch, Mathias Bähr, Ricarda Diem

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Objective: The aim of this study was to investigate the role of voltage-dependent calcium channels (VDCCs) in axon degeneration during autoimmune optic neuritis. Methods: Calcium ion (Ca2+) influx into the optic nerve (ON) through VDCCs was investigated in a rat model of optic neuritis using manganese-enhanced magnetic resonance imaging and in vivo calcium imaging. After having identified the most relevant channel subtype (N-type VDCCs), we correlated immunohistochemistry of channel expression with ON histopathology. In the confirmatory part of this work, we performed a treatment study using ω-conotoxin GVIA, an N-type specific blocker. Results: We observed that pathological Ca2+ influx into ONs during optic neuritis is mediated via N-type VDCCs. By analyzing the expression of VDCCs in the inflamed ONs, we detected an upregulation of α1B, the pore-forming subunit of N-type VDCCs, in demyelinated axons. However, high expression levels were also found on macrophages/activated microglia, and lower levels were detected on astrocytes. The relevance of N-type VDCCs for inflammation-induced axonal degeneration and the severity of optic neuritis was corroborated by treatment with ω-conotoxin GVIA. This blocker led to decreased axon and myelin degeneration in the ONs together with a reduced number of macrophages/activated microglia. These protective effects were confirmed by analyzing the spinal cords of the same animals. Interpretation: We conclude that N-type VDCCs play an important role in inflammation-induced axon degeneration via two mechanisms: First, they directly mediate toxic Ca2+ influx into the axons; and second, they contribute to macrophage/microglia function, thereby promoting secondary axonal damage.

Original languageEnglish
Pages (from-to)81-93
Number of pages13
JournalAnnals of Neurology
Issue number1
StatePublished - Jul 2009
Externally publishedYes


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