Editors' ChoiceSignal Inhibition

Endocannabinoids, mGluR1, Calcium, and G Proteins

Science's STKE  21 Aug 2001:
Vol. 2001, Issue 96, pp. tw2
DOI: 10.1126/stke.2001.96.tw2

Endocannabinoids mediate retrograde signaling at hippocampal synapses. Postsynaptically secreted endocannabinoids act to block presynaptic release of γ-aminobutyric acid (GABA) in a manner termed depolarization-induced suppression of inhibition (DSI). Wilson et al. now provide mechanistic evidence for how this may occur. Hippocampal slices from cannabinoid receptor-1 (CB1)-deficient mice treated with cannabinoid agonists did not exhibit DSI, suggesting that CB1 is the target for retrograde feedback. Also, reduced presynaptic release of GABA was mediated by increased activation of presynaptic G protein βγ subunits that inhibited the activation of N-subtype voltage-dependent calcium channels, whose activation is required for GABA release. Maejima et al. showed that in Purkinje cells, the postsynaptic metabotropic glutamate receptors (mGluR1), which are known to mediate presynaptic inhibition, do so by activating presynaptic CBs. Other experiments suggested that endocannabinoids might not be secreted through normal vesicular release from the postsynaptic membrane. mGluR1-dependent inhibition did not involve measurable changes in postsynaptic calcium concentrations. However, depolarization-induced retrograde suppression did involve calcium flux and was endocannabinoid-dependent. Thus, these data suggest that Purkinje cells can produce retrograde signals by at least two different mechanisms that might interact synergistically.

R. I. Wilson, G. Kunos, R. A. Nicoll, Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31, 453-462 (2001). [Online Journal]

T. Maejima, K. Hashimoto, T. Yoshida, A. Aiba, M. Kano, Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron 31, 463-475 (2001). [Online Journal]