The Journal of Neuroscience, March 16, 2005, ():
Involvement of Cannabinoid Receptors in the Regulation of Neurotransmitter Release in the Rodent Striatum: A Combined Immunochemical and Pharmacological Analysis
J. Neurosci. Köfalvi et al.
25: 2874
Supplemental data
Files in this Data Supplement:
- supplemental material
-
Supplementary Figure 1. Mechanisms by which cannabinoids may inhibit resting and evoked glutamate (Glu) release from striatal nerve terminals. A Although cannabinoids (e.g. WIN55212-2, WIN55212-3, AM251) can directly block voltage dependent NaP+P-channels (yellow) (Nicholson et al., 2003; Liao et al., 2004), and a sodium influx might promote the reversal of the transporter, neither the resting, nor the evoked release of glutamate was dependent on voltage-dependent NaP+P influx, therefore this effect of cannabinoids cannot be responsible for the inhibition of either the uptake/resting release or the evoked glutamate efflux. Also, cannabinoids are known to block NaP+P/KP+P ATPase (dark blue) (Steffens and Feuerstein, 2003) whereby they could slow down the glutamate uptake, which occurs with the inward co-transport of 3 NaP+P ions. However, in this case resting glutamate outflow should have been increased and not decreased as observed in our experiments. Therefore the most likely underlying mechanism for their action is that they directly block the transporter (light green) itself, preventing both the release and the uptake of glutamate. Although the effect of WIN55212-2 was prevented by the CBB1B receptor antagonist AM251, this effect was not stereoselective and persisted in CBB1B -/- mice, indicating that it is independent of CBB1B receptor activation. B WIN5521-2, CP55940, and ?P9P-THC can activate CBB1B receptors (lilac) as well. The activation of CBB1B receptors can be prevented by the CBB1B antagonists SR141716A and AM251. Activated CBB1B receptors via intracellular cascades can close CaP2+P-channels (orange) or may directly inhibit the release machinery. These result in a concomitant inhibition of CaP2+P-dependent glutamate release when the terminal is depolarized. The persistence of the stereoselective effect of WIN55212-2 on evoked release of glutamate in the CBB1B -/- mice provides evidence for the involvement of another, CBB1B-like receptor (gray) as well. This putative cannabinoid-sensitive receptor is activated by CP55940 and WIN55212-2, but only AM251 is able to prevent the action of these drugs at this receptor. SR141716A and probably AM251, its structural analogue, can directly block CaP2+P-channels and voltage-gated NaP+P-channels (yellow; see Discussion), which in turn also inhibits CaP2+P-dependent glutamate release, independently from cannabinoid receptor activation. It should however be noted that in our model, the KP+P-evoked glutamate release was not dependent on voltage-gated NaP+P-channel activation (see Discussion). Green ligand names and arrows indicate activation, red ligand
