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The Journal of Neuroscience, October 15, 1999, 19(20):8765-8777
Cannabinoids Enhance NMDA-Elicited Ca2+ Signals in
Cerebellar Granule Neurons in Culture
Jeffrey G.
Netzeband,
Shannon M.
Conroy,
Kathy L.
Parsons, and
Donna L.
Gruol
Department of Neuropharmacology, The Scripps Research Institute, La
Jolla, California 92037
A physiological role for cannabinoids in the CNS is indicated by
the presence of endogenous cannabinoids and cannabinoid receptors. However, the cellular mechanisms of cannabinoid actions in the CNS have
yet to be fully defined. In the current study, we identified a novel
action of cannabinoids to enhance intracellular Ca2+
responses in CNS neurons. Acute application of the cannabinoid receptor
agonists R(+)-methanandamide, R(+)-WIN,
and HU-210 (1-50 nM) dose-dependently enhanced the peak
amplitude of the Ca2+ response elicited by
stimulation of the NMDA subtype of glutamate receptors (NMDARs)
in cerebellar granule neurons. The cannabinoid effect was blocked by
the cannabinoid receptor antagonist SR141716A and the
Gi/Go protein inhibitor pertussis toxin
but was not mimicked by the inactive cannabinoid analog
S( )-WIN, indicating the involvement of cannabinoid
receptors. In current-clamp studies neither R(+)-WIN nor
R(+)-methanandamide altered the membrane response to
NMDA or passive membrane properties of granule neurons, suggesting that
NMDARs are not the primary sites of cannabinoid action. Additional Ca2+ imaging studies showed that cannabinoid
enhancement of the Ca2+ signal to NMDA did not
involve N-, P-, or L-type Ca2+ channels but was
dependent on Ca2+ release from intracellular stores.
Moreover, the phospholipase C inhibitor U-73122 and the inositol
1,4,5-trisphosphate (IP3) receptor antagonist
xestospongin C blocked the cannabinoid effect, suggesting that the
cannabinoid enhancement of NMDA-evoked Ca2+ signals
results from enhanced release from IP3-sensitive
Ca2+ stores. These data suggest that the CNS
cannabinoid system could serve a critical modulatory role in CNS
neurons through the regulation of intracellular Ca2+ signaling.
Key words:
cannabinoid; methanandamide; WIN; HU-210; cerebellum; granule neuron; NMDA; intracellular calcium
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208765-13$05.00/0
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