A Role for Caveolae/Lipid Rafts in the Uptake and Recycling of the Endogenous Cannabinoid Anandamide

McFarland, Matthew J.; Porter, Amy C.; Rakhshan, Fariborz; Rawat, Diwan S.; Gibbs, Richard A.; Barker, Eric L.

doi:10.1074/jbc.m407250200

Cited by 124 publications

(158 citation statements)

References 44 publications

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“…Interestingly, it has been suggested that eCB uptake involves caveolae-related endocytosis (45), and caveolin-1, which is a marker for caveolae, displays properties similar to a fatty acid-binding protein (46). Because AEA-induced depression requires synaptic activity, but does not appear to require receptor or channel activation, it is possible that paired-pulse stimulation simply affects the physical state of the cell plasma membrane lipid bilayer in a way that modulates the transmembrane transport, which was previously reported for carrier-mediated transport of 5-hydroxytryptamine (47).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…However, the mechanism of CB1R internalization is not completely understood although recent findings suggest that both clathrin-coated pits and caveolae might be involved in this process [13]. In addition, it has been shown that the cellular accumulation of its ligand AEA is possibly due to caveolae-mediated endocytosis in RBL-2H3 cells [14] and that methyl-b-cyclodextrin (MCD), which extracts cholesterol from the plasma membrane, completely blocks AEA-induced cell death in a variety of cells, including PC12, C6, HEK and HL-60 cells [15]. All these data point towards an involvement of caveolae and of cholesterol-enriched membrane domains in the trafficking Abbreviations: AEA, anandamide; Cav1, caveolin 1; DRMs, detergent-resistant microdomains; MCD, methyl-b-cyclodextrin; GPCRs, G-protein-coupled receptors; TNE/TX-100, Tris Na EDTA/Triton X-100 buffer; PBS, phosphate buffer saline and function of CB1R.…”

Section: Introductionmentioning

confidence: 99%

Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells

Sarnataro¹,

Grimaldi²,

Pisanti³

et al. 2005

FEBS Letters

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In this report we show, by confocal analysis of indirect immunofluorescence, that the type-1 cannabinoid receptor (CB1R), which belongs to the family of G-protein-coupled receptors, is expressed on the plasma membrane in human breast cancer MDA-MB-231 cells. However, a substantial proportion of the receptor is present in lysosomes. We found that CB1R is associated with cholesterol-and sphyngolipid-enriched membrane domains (rafts). Cholesterol depletion by methyl-b-cyclodextrin (MCD) treatment strongly reduces the flotation of the protein on the raft-fractions (DRM) of sucrose density gradients suggesting that CB1 raft-association is cholesterol dependent. Interestingly binding of the agonist, anandamide (AEA) also impairs DRM-association of the receptor suggesting that the membrane distribution of the receptor is dependent on rafts and is possibly regulated by the agonist binding. Indeed MCD completely blocked the clustering of CB1R at the plasma membrane. On the contrary the lysosomal localization of CB1R was impaired by this treatment only after AEA binding.

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“…In contrast, AEA is an uncharged lipid capable of traversing the bilayer unaided (10). Accordingly, several studies concluded that AEA uptake occurs by passive diffusion (10)(11)(12)(13)(14)(15), although facilitated diffusion and/or endocytosis have also been proposed (16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

Identification of intracellular carriers for the endocannabinoid anandamide

Kaczocha¹,

Glaser

Deutsch³

2009

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

311

332

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The endocannabinoid anandamide (arachidonoyl ethanolamide, AEA) is an uncharged neuromodulatory lipid that, similar to many neurotransmitters, is inactivated through its cellular uptake and subsequent catabolism. AEA is hydrolyzed by fatty acid amide hydrolase (FAAH), an enzyme localized on the endoplasmic reticulum. In contrast to most neuromodulators, the hydrophilic cytosol poses a diffusional barrier for the efficient delivery of AEA to its site of catabolism. Therefore, AEA likely traverses the cytosol with the assistance of an intracellular carrier that increases its solubility and rate of diffusion. To study this process, AEA uptake and hydrolysis were examined in COS-7 cells expressing FAAH restricted to the endoplasmic reticulum, mitochondria, or the Golgi apparatus. AEA hydrolysis was detectable at the earliest measurable time point (

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A Role for Caveolae/Lipid Rafts in the Uptake and Recycling of the Endogenous Cannabinoid Anandamide

Cited by 124 publications

References 44 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

Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells

Identification of intracellular carriers for the endocannabinoid anandamide

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