Effects of Cannabinoids on Voltage Gated Ion Channels 211

Calcium Channels

In the majority of studies, cannabinoids depressed voltage-dependent calcium channels. According to the first observations, activation of CB1 receptors inhibits N-type voltage-dependent calcium channels in neuronal cell lines (Caulfield and Brown 1992; Mackie and Hille 1992; Mackie et al. 1993). No inhibition occurred in pertussis toxin-treated cells, indicating the involvement of G proteins containing G«i/0 subunits. Later, this observation was extended to isolated rat hippocampal neurons and cerebellar granule cells (Twitchell et al. 1997; Nogueron et al. 2001). In isolated rat sympathetic ganglion neurons that previously had been injected with CB1 receptor cRNA, cannabinoids also inhibited N-type calcium channels (Pan et al. 1996). Q-type calcium channels were also inhibited in CB1 receptor-transfected AtT20 cells (Mackie et al. 1995). The endogenous cannabinoid (endocannabinoid) anandamide inhibits T-type calcium channels; this effect is, however, not mediated by CB1 receptors (Chemin et al. 2001).

There are at least two examples for stimulation of calcium channels by cannabinoids: L-type calcium currents in a neuronal cell line (Rubovitch et al. 2002) and in retinal rods of the tiger salamander (Straiker and Sullivan 2003) were enhanced by cannabinoids.

Potassium Channels

Activated CB1 receptors can also change the function of several types of potassium channels. In oocytes and AtT20 cells artificially expressing the CB1 receptor, stimulation of inwardly rectifying potassium channels was repeatedly observed (Henry and Chavkin 1995; Mackie et al. 1995; Garcia et al. 1998; McAllister et al. 1999). Potassium A currents in cultured hippocampal neurons are stimulated by cannabinoids (Deadwyler et al. 1995; Mu et al. 2000). The effects of cannabinoids on potassium M currents in hippocampal brain slices have also been studied; M currents were inhibited, which means an enhancement of neuronal excitability (Schweitzer 2000). The potassium K current is inhibited by cannabinoids in cultured hippocampal neurons (Hampson et al. 2000). As in the case of calcium channels, anandamide can elicit a CB1 receptor-independent effect on potassium channels, i.e. it inhibits the acid-sensitive background potassium channel TASK-1 (Maingret et al. 2001).

Sodium Channels

In an early study, Turkanis et al. (1991) showed that ^-tetrahydrocannabinol inhibits voltage-dependent sodium channels; the involved primary receptor was not identified in this study. More recently, it was observed that anandamide and the synthetic CB1/CB2 receptor agonist WIN55212-2 inhibited voltage-dependent sodium channels in synaptosomes prepared from mouse brain (Nicholson et al. 2003). Since the effects were not attenuated by the CB1 receptor antagonist AM251, the involvement of CB1 receptors can be excluded.

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