Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels

Stelt, Mario van der; Trevisani, Marcello; Vellani, Vittorio; Petrocellis, Luciano De; Moriello, Aniello Schiano; Campi, Barbara; McNaughton, Peter A.; Geppetti, P; Marzo, Vincenzo Di

doi:10.1038/sj.emboj.7600784

Cited by 218 publications

(128 citation statements)

References 52 publications

(75 reference statements)

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“…AEA-induced depression of EPSC amplitude was decreased when the temperature was reduced, and depression was inhibited by intracellular loading with the AMT blockers, VDM11 and UCM707, which is in line with previous reports on AEA release and uptake (2,18,21,25,26). The finding by Van der Stelt et al (43), that AMT blockers produce cellular buildup of AEA, provides additional support for transporter-mediated release. Furthermore, the fact that AEA-induced depression required paired-pulse stimulation does not support the theory that eCB transport is solely dependent on the concentration gradient across the membrane.…”

Section: Discussionsupporting

confidence: 80%

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Adermark

Lovinger

2007

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoids (eCBs) mediate short-and long-term depression of synaptic strength by retrograde transsynaptic signaling. Previous studies have suggested that an eCB mobilization or release step in the postsynaptic neuron is involved in this retrograde signaling. However, it is not known whether this release process occurs automatically upon eCB synthesis or whether it is regulated by other synaptic factors. To address this issue, we loaded postsynaptic striatal medium spiny neurons (MSNs) with the eCBs anandamide (AEA) or 2-arachidonoylglycerol and determined the conditions necessary for presynaptic inhibition. We found that presynaptic depression of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitory postsynaptic currents (IPSCs) induced by postsynaptic eCB loading required a certain level of afferent activation that varied between the different synaptic types. Synaptic depression at excitatory synapses was temperature-dependent and blocked by the eCB membrane transport blockers, VDM11 and UCM707, but did not require activation of metabotropic glutamate receptors, L-calcium channels, nitric oxide, voltage-activated Na ؉ channels, or intracellular calcium. Application of the CB1R antagonist, AM251, after depression was established, reversed the decrease in EPSC, but not in IPSC, amplitude. Direct activation of the CB1 receptor by WIN 55,212-2 initiated synaptic depression that was independent of afferent stimulation. These findings indicate that retrograde eCB signaling requires a postsynaptic release step involving a transporter or carrier that is activated by afferent stimulation/synaptic activation.anandamide ͉ basal ganglia ͉ synaptic plasticity ͉ CB1 receptor C hanges in synaptic strength, such as depolarization-induced suppression of excitatory (DSE) or depolarization-induced suppression of inhibitory (DSI) transmission and long-term depression (LTD), can be induced by retrograde endocannabinoid (eCB) signaling (1-3). eCB production and release can be triggered by depolarization (4-6) or neurotransmitter-induced increases in intracellular calcium concentration and after activation of G protein-coupled receptors (7, 8) or voltage-gated calcium channels (9). Postsynaptically released eCBs produce synaptic depression presumably by binding to presynaptic cannabinoid 1 receptors (CB 1 Rs) and decreasing the probability of neurotransmitter release either in a transient or sustained manner (2, 3, 10-12).The two best characterized eCBs are N-arachidonoylethanolamide [anandamide (AEA)] and 2-arachidonoylglycerol (2-AG), which are synthesized from membrane-derived lipid precursors (13,14). Diffusion and cellular uptake of both AEA and 2-AG are believed to be facilitated by an AEA transporter (AMT) (6,8,(15)(16)(17)(18), although it has been suggested that there is no need for such a transporter (19,20). AEA transport is cell-specific, unaffected by metabolic inhibitors, temperature-dependent, energy-and sodiumindependent, and believed to involve a protein carrier molecule (18,21). Inhib...

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Section: Discussionsupporting

confidence: 80%

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Adermark

Lovinger

2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Considering its lower affinity for TRPV1 than CB 1 receptors (Ahluwalia et al, 2003a,b;Ross, 2003), short half-life, and lipophilic nature, AEA is likely to bind to TRPV1 receptors close to its site of synthesis inside the same neuron. This has been demonstrated by the measurement of TRPV1-mediated currents activated from within individual DRG cells by intracellular AEA produced in response to rising [Ca 2ϩ ] i (triggered by depletion of intracellular calcium stores) (van der Stelt et al, 2005) or capsaicin (Millns et al, 2006), consistent with the enhancing effects of URB597-on TRPV1-dependent cobalt uptake in this study. Together, these data provide functional evidence for the coexistence of FAAH, AEA, and TRPV1 in DRG neurons.…”

Section: Discussionsupporting

confidence: 66%

“…Neurons that produce AEA are also likely to contain FAAH (van der Stelt et al, 2005;Millns et al, 2006). In rodent CNS, this status is supported by the proximity of FAAH-immunoreactive (IR) neurons to AEA-responsive CBRs (Egertová et al, 1998Gulyas et al, 2004).…”

Section: Introductionmentioning

confidence: 90%

“…These neurons express vanilloid type 1 transient receptor potential (TRPV1) receptors that are activated by capsaicin and noxious heat and are critical to the development of inflammatory thermal hyperalgesia (Caterina et al, 1997(Caterina et al, , 2000. AEA production has been measured in capsaicin-sensitive DRG neurons and can excite DRG neurons intracellularly by activation of TRPV1 receptors (Ahluwalia et al, 2003a;van der Stelt et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Localization of the Endocannabinoid-Degrading Enzyme Fatty Acid Amide Hydrolase in Rat Dorsal Root Ganglion Cells and Its Regulation after Peripheral Nerve Injury

Lever¹,

Robinson²,

Cibelli³

et al. 2009

J. Neurosci.

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Fatty acid amide hydrolase (FAAH) is a degradative enzyme for a group of endogenous signaling lipids that includes anandamide (AEA).AEA acts as an endocannabinoid and an endovanilloid by activating cannabinoid and vanilloid type 1 transient receptor potential (TRPV1) receptors, respectively, on dorsal root ganglion (DRG) sensory neurons. Inhibition of FAAH activity increases AEA concentrations in nervous tissue and reduces sensory hypersensitivity in animal pain models. Using immunohistochemistry, Western blotting, and reverse transcription-PCR, we demonstrate the location of the FAAH in adult rat DRG, sciatic nerve, and spinal cord. In naive rats, FAAH immunoreactivity localized to the soma of 32.7 Ϯ 0.8% of neurons in L4 and L5 DRG. These were small-sized (mean soma area, 395.96 Ϯ 5.6 m 2 ) and predominantly colabeled with peripherin and isolectin B4 markers of unmyelinated C-fiber neurons; 68% colabeled with antibodies to TRPV1 (marker of nociceptive DRG neurons), and Ͻ2% colabeled with NF200 (marker of large myelinated neurons). FAAH-IR was also present in small, NF200-negative cultured rat DRG neurons. Incubation of these cultures with the FAAH inhibitor URB597 increased AEA-evoked cobalt uptake in a capsazepine-sensitive manner. After sciatic nerve axotomy, there was a rightward shift in the cell-size distribution of FAAH-immunoreactive (IR) DRG neurons ipsilateral to injury: FAAH immunoreactivity was detected in larger-sized cells that colabeled with NF200. An ipsilateral versus contralateral increase in both the size and proportion of FAAH-IR DRG occurred after spinal nerve transection injury but not after chronic inflammation of the rat hindpaw 2 d after injection of complete Freund's adjuvant. This study reveals the location of FAAH in neural tissue involved in peripheral nociceptive transmission.

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“…Activation of CB 1 usually leads to a decrease in intracellular calcium in presynaptic terminals (Mackie and Hille, 1992) and, thereby, to a reduced transmitter release (Freund et al, 2003). Activation of TRPV1 by anandamide, in contrast, promotes Ca 2ϩ influx in postsynaptic sites (van der Stelt et al, 2005). These observations led to the hypothesis that TRPV1 and CB 1 might exert opposite effects on certain brain functions, including emotionality, cognition, and synaptic plasticity (Di Marzo et al, 2001a;Cristino et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Reduced Anxiety, Conditioned Fear, and Hippocampal Long-Term Potentiation in Transient Receptor Potential Vanilloid Type 1 Receptor-Deficient Mice

Marsch¹,

Foeller²,

Rammes³

et al. 2007

J. Neurosci.

308

230

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The transient receptor potential vanilloid type 1 channel (TRPV1) (formerly called vanilloid receptor VR1) is known for its key role of functions in sensory nerves such as perception of inflammatory and thermal pain. Much less is known about the physiological significance of the TRPV1 expression in the brain. Here we demonstrate that TRPV1 knock-out mice (TRPV1-KO) show less anxiety-related behavior in the light-dark test and in the elevated plus maze than their wild-type littermates with no differences in locomotion. Furthermore, TRPV1-KO mice showed less freezing to a tone after auditory fear conditioning and stress sensitization. This reduction of conditioned and sensitized fear could not be explained by alterations in nociception. Also, tone perception per se was unaffected, as revealed by determination of auditory thresholds through auditory brainstem responses and distortion-product otoacoustic emissions. TRPV1-KO showed also less contextual fear if assessed 1 d or 1 month after strong conditioning protocols. These impairments in hippocampusdependent learning were mirrored by a decrease in long-term potentiation in the Schaffer collateral-commissural pathway to CA1 hippocampal neurons. Our data provide first evidence for fear-promoting effects of TRPV1 with respect to both innate and conditioned fear and for a decisive role of this receptor in synaptic plasticity.

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Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels

Cited by 218 publications

References 52 publications

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Retrograde endocannabinoid signaling at striatal synapses requires a regulated postsynaptic release step

Localization of the Endocannabinoid-Degrading Enzyme Fatty Acid Amide Hydrolase in Rat Dorsal Root Ganglion Cells and Its Regulation after Peripheral Nerve Injury

Reduced Anxiety, Conditioned Fear, and Hippocampal Long-Term Potentiation in Transient Receptor Potential Vanilloid Type 1 Receptor-Deficient Mice

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