Abstract
Endocannabinoids are known as retrograde messengers, being released from the postsynaptic neuron and acting on specific presynaptic G-protein-coupled cannabinoid (CB) receptors to decrease neurotransmitter release. Also, at physiologically relevant concentrations cannabinoids can directly modulate the function of voltage-gated and receptor-operated ion channels. Using patch-clamp recording we analyzed the consequences of the direct action of an endocannabinoid, 2-arachidonoylglycerol (2-AG), on the functional properties of glycine receptor channels (GlyRs) and ionic currents in glycinergic synapses. At physiologically relevant concentrations (0.1–1 μM), 2-AG directly affected the functions of recombinant homomeric α1H GlyR: it inhibited peak amplitude and dramatically enhanced desensitization. The action of 2-AG on GlyR-mediated currents developed rapidly, within ∼300 ms. Addition of 1 μM 2-AG strongly facilitated the depression of glycine-induced currents during repetitive (4–10 Hz) application of short (2 ms duration) pulses of glycine to outside-out patches. In brainstem slices from CB1 receptor knockout mice, 2-AG significantly decreased the extent of facilitation of synaptic currents in hypoglossal motoneurons during repetitive (10–20 Hz) stimulation. These observations suggest that endocannabinoids can modulate postsynaptic metaplasticity of glycinergic synaptic currents in a CB1 receptor-independent manner.
Highlights
Cannabinoids have widespread actions in the brain: they influence learning and memory, modulate locomotor activity and reward pathways
To test whether the direct modulation of the glycine-induced current (GlyR) desensitization by endocannabinoids contributes to the activity–dependent changes in glycinergic transmission we performed experiments in hypoglossal motoneurons (HM) using the CB1R−/− mouse brainstem slice preparation
This model eliminates the possible impact of presynaptic retrograde modulation by endocannabinoids
Summary
Cannabinoids have widespread actions in the brain: they influence learning and memory, modulate locomotor activity and reward pathways. Majority of its effects suggested to be mediated by specific G-protein-coupled cannabinoid receptors (CBRs), their endogenous ligands (endocannabinoids) and the cellular machinery for their synthesis and degradation. Endocannabinoids are thought to act as retrograde messengers, being released from the postsynaptic neuron and acting on presynaptic CBRs to decrease neurotransmitter release (Wilson and Nicoll, 2001). Numerous studies have reported the existence of functionally important target(s) for brain cannabinoid signaling in addition to CBRs. numerous studies have reported the existence of functionally important target(s) for brain cannabinoid signaling in addition to CBRs These include various voltage- and ligand-gated ion channels and in particular, the Cys-loop receptor superfamily, namely the nicotinic, the serotonin and the glycine (GlyR) receptors (for review see Oz, 2006). The functional implications of the direct effects of endocannabinoids are poorly studied
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