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Br J Pharmacol. 2014 Jan;171(1):158-70. doi: 10.1111/bph.12436.

Riluzole activates TRPC5 channels independently of PLC activity.

Author information

1
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany.

Abstract

BACKGROUND AND PURPOSE:

The transient receptor potential channel C5 (TRPC5) is a Ca(2+)-permeable cation channel, which is predominantly expressed in the brain. TRPC5 is activated in a PLC-dependent manner by, as yet, unidentified endogenous messengers. Recently, modulators of TRPC5, like Ca(2+), pH and phospholipids, have been identified. However, the role of TRPC5 in vivo is only poorly understood. Novel specific modulators of TRPC5 might help to elucidate its function.

EXPERIMENTAL APPROACH:

Novel modulators of TRPC5 were identified in a compound screening of approved drugs and natural compounds. The potency and selectivity of TRPC5-activating compounds were determined by fluorometric calcium imaging. The biophysical properties of channel activation by these compounds were analysed using electrophysiological measurements.

KEY RESULTS:

Riluzole was identified as a novel activator of TRPC5 (EC₅₀ 9.2 ± 0.5 μM) and its mechanism of action was shown to be independent of G protein signalling and PLC activity. Riluzole-induced TRPC5 currents were potentiated by La(3+) and, utilizing TRPC5 mutants that lack La(3+) binding sites, it was confirmed that riluzole and La(3+) activate TRPC5 by different mechanisms. Recordings of excised inside-out patches revealed a relatively direct effect of riluzole on TRPC5.

CONCLUSIONS AND IMPLICATIONS:

Riluzole can activate TRPC5 heterologously expressed in HEK293 cells as well as those endogenously expressed in the U-87 glioblastoma cell line. Riluzole does not activate any other member of the TRPC family and could, therefore, despite its action on other ion channels, be a useful pharmacological tool for identifying TRPC5-specific currents in immortalized cell lines or in acutely isolated primary cells.

KEYWORDS:

TRPC5; calcium imaging; patch clamp electrophysiology; riluzole

PMID:
24117252
PMCID:
PMC3874704
DOI:
10.1111/bph.12436
[Indexed for MEDLINE]
Free PMC Article
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