Activated T-cells inhibit neurogenesis by releasing granzyme B: Rescue by Kv1.3 blockers

Tongguang Wang, Myoung Hwa Lee, Tory Johnson, Rameeza Allie, Lina Hu, Peter A. Calabresi, Avindra Nath

Research output: Contribution to journalArticle

Abstract

There is a great need for pharmacological approaches to enhance neural progenitor cell (NPC) function particularly in neuroinflammatory diseases with failed neuroregeneration. In diseases such as multiple sclerosis and stroke, T-cell infiltration occurs in periventricular zones where NPCs are located and is associated with irreversible neuronal loss.We studied the effect of T-cellactivation on NPC functions. NPC proliferation and neuronal differentiation were impaired by granzyme B (GrB) released by the T-cells. GrB mediated its effects by the activation of a Gi-protein-coupled receptor leading to decreased intracellular levels of cAMP and subsequent expression of the voltagedependent potassium channel, Kv1.3. Importantly, blocking channel activity with margatoxin or blocking its expression reversed the inhibitory effects of GrB on NPCs. We have thus identified a novel pathway in neurogenesis. The increased expression of Kv1.3 in pathological conditions makes it a novel target for promoting neurorestoration.

Original languageEnglish (US)
Pages (from-to)5020-5027
Number of pages8
JournalJournal of Neuroscience
Volume30
Issue number14
DOIs
StatePublished - Apr 7 2010

ASJC Scopus subject areas

  • Neuroscience(all)

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