TRPC5 belongs to the canonical transient receptor potential channels (TRPC), which form non-selective calcium-permeable cation channels. Phylogenetic analysis revealed that TRPC proteins can be subdivided into three groups: TRPC1/C4/C5, TRPC3/C6/C7 and TRPC2. Within these subfamilies, the proteins can assemble as homotetramers or heterotetramers, generating ion channels with unique biophysical properties (Strubing et al., 2001; Hofmann et al., 2002). Heterologous co-expression studies of TRPC1 and TRPC5 demonstrate an altered current–voltage relationship and a distinct single channel conductance compared with homomeric TRPC5 currents. The interaction of TRPC1 and TRPC5 was further confirmed by intermolecular FRET measurements in heterologous expression systems and by co-immunoprecipitations studies performed on isolated rat brains (Goel et al., 2002; Hofmann et al., 2002; Strubing et al., 2003). TRPC5 is predominantly found in the CNS. In situ hybridization staining indicate its highest levels of expression in the hippocampus, olfactory bulb and in the amygdala (Lein et al., 2007) (http://mouse.brain-map.org). Other tissues like gonads, heart, liver and vascular smooth muscle exhibit low expression levels of TRPC5 (Riccio et al., 2002; Beech et al., 2004; Fowler et al., 2007). Recently, TRPC5 has been assigned a function in the regulation of the morphology and motility of neuronal growth cones and neurite length, as well as contributing to neurotransmitter release (Greka et al., 2003; Munsch et al., 2003; Hui et al., 2006). Furthermore, TRPC5-knockout mice exhibit diminished fear-related behaviour when confronted with innate aversive stimuli (Riccio et al., 2009). The limited knowledge about the physiological function of TRPC5 is partially ascribable to the fact that there are, as yet, no known endogenous specific activators of TRPC5. Like all TRPC channels, TRPC5 can be indirectly activated by the stimulation of Gαq-linked receptors or growth factor receptors, which are coupled to PLC (Schaefer et al., 2000; Putney, Jr, 2004). However, in contrast to TRPC3/C6/C7, TRPC5 is not directly gated by DAG, which is generated from phosphatidylinositol 4,5-bisphosphate (PIP2) by PLC. Several diverse stimuli have been identified to modulate TRPC5 channel activity. Elevated intracellular calcium concentrations (Blair et al., 2009), increased extracellular acidity (Semtner et al., 2007) and phospholipids like PIP2 (Otsuguro et al., 2008) and lysophosphatidylcholine (which is assumed to distort the lipid bilayer) (Flemming et al., 2006), have been reported to mediate TRPC5 activity. Moreover, metal ions like lead (Sukumar and Beech, 2010), and μM concentrations of trivalent lanthanides (La3+, Gd3+) can induce or augment TRPC5 currents (Jung et al., 2003). Recently, genistein and rosiglitazone have also been shown to activate TRPC5 channels, independently of classical receptor activation (Wong et al., 2010; Majeed et al., 2011). To improve the understanding of the physiological relevance of TRPC5 and to address the channel pharmacologically, specific and potent modulators are required. In the present study, we identified and analysed riluzole [6-(trifluoromethoxy) benzothiazol-2-amine] as a novel TRPC5 activator. Riluzole is the only approved drug which delays the progression of amyotrophic lateral sclerosis (ALS) a motoneuron disease associated with an increased glutamate concentration (Lacomblez et al., 1996; Schuster et al., 2012). A number of recent studies have also proposed a clinical use for riluzole in psychiatric disorders due to its antidepressant properties (Pittenger et al., 2008; Grant et al., 2010). At the molecular level, riluzole has been shown to affect the activity of several ion channels. It is reported to block voltage-gated sodium channels (<1–10 μM) and to inhibit voltage-activated calcium channels (10–40 μM), thereby preventing repetitive neuronal firing and promoting neuronal survival (Huang et al., 1997; Song et al., 1997; Wang et al., 2008). Riluzole also potentiates calcium-dependent potassium currents [2–20 μM; (Wu and Li, 1999)] and has been shown to activate K2P2.1 (TREK1) and K2P4.1 (TRAAK) channels (100 μM), two members of the 2-pore K+ channels (Duprat et al., 2000). For an extensive review of the effects of riluzole on ion channels, see Bellingham (2011). Here, we show that riluzole can also activate TRPC5 channels, heterologously expressed in HEK293 cells as well as endogenously expressed TRPC5 in the U-87 glioblastoma cell line. The activation mechanism was shown to be independent of cytosolic components like PLC activity or of intracellular calcium stores, indicating that riluzole has a rather direct effect on TRPC5.