Tag Archives: cannabinoid receptors

Dissecting the signaling pathways involved in the crosstalk between mGlu5 and CB1 receptors.

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“The metabotropic glutamate (mGlu) receptor 5 and the cannabinoid type 1 (CB1) receptor are G-protein-coupled receptors (GPCR) that are widely expressed in the central nervous system (CNS). mGlu5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, while the CB1 receptor, mainly present at presynaptic terminals, is coupled to the Gi/o protein and triggers an inhibitory response. Recent studies suggest that the glutamatergic and endocannabinoid systems exhibit a functional interaction to modulate several neural processes. In this review we discuss possible mechanisms involved in this crosstalk and its relationship with physiological and pathological conditions, including nociception, addiction and fragil X syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/27338080

Anatomical characterization of the cannabinoid cb1 receptor in cell type-specific mutant mouse rescue models.

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“Type-1 cannabinoid (CB1 ) receptors are widely distributed in the brain. Their physiological roles depend on their distribution pattern that differs remarkably among cell types. Hence, subcellular compartments with little but functional relevant CB1 receptors can be overlooked, fostering an incomplete mapping. To overcome this, knock-in mice with cell-type specific rescue of CB1 receptors have emerged as excellent tools to investigate its cell type-specific localization and sufficient functional role with no bias.

However, to know whether these rescue mice maintain endogenous CB1 receptor expression level, detailed anatomical studies are called for. The subcellular distribution of hippocampal CB1 receptors of rescue mice that express the gene exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1 -RS) or GABAergic neurons (GABA-CB1 -RS) was studied by immunoelectron microscopy. Results were compared with conditional CB1 receptor knock-out lines.

As expected, CB1immunoparticles appeared at presynaptic plasmalemma making asymmetric and symmetric synapses. In the hippocampal CA1 stratum radiatum, the values of the CB1 receptor immunopositive excitatory and inhibitory synapses were: Glu-CB1 -RS: 21.89% (glutamatergic terminals); 2.38% (GABAergic terminals); GABA-CB1 -RS: 1.92% (glutamatergic terminals); 77.92% (GABAergic terminals). The proportion of CB1 receptor immunopositive excitatory and inhibitory synapses in the inner third of the dentate molecular layer was: Glu-CB1 -RS: 53.19% (glutamatergic terminals); 2.30% (GABAergic terminals); GABA-CB1 -RS: 3.19% (glutamatergic terminals); 85.07% (GABAergic terminals).

Taken together, Glu-CB1 -RS and GABA-CB1 -RS mice show the usual CB1 receptor distribution and expression in hippocampal cell types with specific rescue of the receptor, being therefore ideal for in-depth anatomical and functional investigations of the endocannabinoid system.”

http://www.ncbi.nlm.nih.gov/pubmed/27339436

The multiple waves of cannabinoid 1 receptor signaling.

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“The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptor (GPCR) in the CNS with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB1Rs may signal in three different spatiotemporal waves.

The first wave is transient (<10 minutes) and is initiated by heterotrimeric G proteins followed by a second wave (>10 minutes) mediated by beta-arrestins. A final third wave occurs at intracellular compartments and could be elicited by G proteins or beta-arrestins.

This functional complexity presents multiple challenges, from the correct classification of receptor ligands to the identification of the signaling pathways regulated by each wave and their underlying molecular mechanisms and physiological impact.

Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system.

Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from CB1R. The identification of mutations in the receptor that can bias signaling to specific pathways and the use of siRNA technology in combination with toxins have been key tools to identify which signaling cascades are controlled by G proteins or beta-arrestins.

Here, we review our current knowledge of the multiple waves of CB1R signaling with particular emphasis on the mechanisms and cascades mediated by beta-arrestins downstream from the CB1R.”

http://www.ncbi.nlm.nih.gov/pubmed/27338082

Activation of the orphan receptor GPR55 by lysophosphatidylinositol promotes metastasis in triple-negative breast cancer.

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Image result for Oncotarget.“The orphan G protein-coupled receptor GPR55 has been directly or indirectly related to basic alterations that drive malignant growth: uncontrolled cancer cell proliferation, sustained angiogenesis, and cancer cell adhesion and migration. However, little is known about the involvement of this receptor in metastasis.

Here, we show that elevated GPR55 expression in human tumors is associated with the aggressive basal/triple-negative breast cancer population, higher probability to develop metastases, and therefore poor patient prognosis. Activation of GPR55 by its proposed endogenous ligand lysophosphatidylinositol confers pro-invasive features on breast cancer cells both in vitro and in vivo. Specifically, this effect is elicited by coupling to Gq/11 heterotrimeric proteins and the subsequent activation, through ERK, of the transcription factor ETV4/PEA3.

Together, these data show that GPR55 promotes breast cancer metastasis, and supports the notion that this orphan receptor may constitute a new therapeutic target and potential biomarker in the highly aggressive triple-negative subtype.”

http://www.ncbi.nlm.nih.gov/pubmed/27340777

Effects of activation of endocannabinoid system on myocardial metabolism.

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“Endocannabinoids exert their effect on the regulation of energy homeostasis via activation of specific receptors. They control food intake, secretion of insulin, lipids and glucose metabolism, lipid storage. Long chain fatty acids are the main myocardial energy substrate. However, the heart exerts enormous metabolic flexibility emphasized by its ability to utilzation not only fatty acids, but also glucose, lactate and ketone bodies. Endocannabinoids can directly act on the cardiomyocytes through the CB1 and CB2 receptors present in cardiomyocytes. It appears that direct activation of CB1 receptors promotes increased lipogenesis, pericardial steatosis and bioelectrical dysfunction of the heart. In contrast, stimulation of CB2 receptors exhibits cardioprotective properties, helping to maintain appropriate amount of ATP in cardiomyocytes. Furthermore, the effects of endocannabinoids at both the central nervous system and peripheral tissues, such as liver, pancreas, or adipose tissue, resulting indirectly in plasma availability of energy substrates and affects myocardial metabolism. To date, there is little evidence that describes effects of activation of the endocannabinoid system in the cardiovascular system under physiological conditions. In the present paper the impact of metabolic diseases, i. e. obesity and diabetes, as well as the cardiovascular diseases – hypertension, myocardial ischemia and myocardial infarction on the deregulation of the endocannabinoid system and its effect on the metabolism are described.”

http://www.ncbi.nlm.nih.gov/pubmed/27333924

Cannabinoids and Neuro-Inflammation: Regulation of Brain Immune Response.

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“Cannabinoid receptors are involved in neurophatogenic mechanisms of inflammatory disorders of the central nervous system and their expression can be modulated during the disease.

Brain inflammatory processes are characterized by infiltration of numerous types of cells, peripheral immune cells, brain resident immune cells, the microglial cells and numerous other neuronal cells. The disruption of the blood brain barrier favours cell infiltration in the central nervous system with consequent neuronal damage, common event in many neuro-inflammatory diseases.

In this review we evidence the role of cannabinoid receptor, their expression at peripheral and central levels in order to better understand their implication in neuro-inflammation.

Cannabinoids affect brain adaptive and immune response, have regulatory action on inflammatory mediators and can exert a role in blood brain barrier damage prevention.

Furthermore, in numerous neurodegenerative diseases with inflammatory component the beneficial effects of cannabinoids have been widely reported, so current knowledge of cannabinoid involvement in these central nervous system disorders are also reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/27334610

Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders.

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“Agents acting via cannabinoid receptors have been widely developed; starting from the chemical structure of phytocannabinoids isolated from cannabis sativa plant, specific and selective compounds of these receptors have been produced ranging from partial to full agonists and /or antagonists endowed with different potency.

The enhanced interest on developing such classes of drugs is due to the beneficial properties widely reported by both anecdotal reports and scientific studies describing the potential medicinal use of cannabinoids and their derivatives in numerous pathological conditions in both in vitro and in vivo models.

The use of these drugs has been found to be of benefit in a wide number of neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases, just to mention some.

In particular, being the cannabinoid CB1 receptor a central receptor expressed by neurons of the central nervous system, the attention for the treatment of neurological diseases has been mainly focused on compounds acting via this receptor, however some of these compounds has been showed to act by alternative pathways in some cases unrelated to CB1 receptors.

Nonetheless, endocannabinoids are potent regulators of the synaptic function in the central nervous system and their levels are modulated in neurological diseases.

In this study, we focused on endocannabinoid mechanism of action in neuronal signaling and on cannabimimetic drug potential application in neurological disorders.

Finally, novel patents on cannabis-based drugs with applicability in central nervous system disorders are highlighted, to suggest future potential therapeutic utility of derivatives of this ancient plant.”

http://www.ncbi.nlm.nih.gov/pubmed/27334611

Harnessing the Endocannabinoid 2-Arachidonoylglycerol to Lower Intraocular Pressure in a Murine Model.

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“Cannabinoids, such as Δ9-THC, act through an endogenous signaling system in the vertebrate eye that reduces IOP via CB1 receptors.

Endogenous cannabinoid (eCB) ligand, 2-arachidonoyl glycerol (2-AG), likewise activates CB1 and is metabolized by monoacylglycerol lipase (MAGL). We investigated ocular 2-AG and its regulation by MAGL and the therapeutic potential of harnessing eCBs to lower IOP.

Our data confirm a central role for MAGL in metabolism of ocular 2-AG and related lipid species, and that endogenous 2-AG can be harnessed to reduce IOP. The MAGL blocker KML29 has promise as a therapeutic agent, while JZL184 may have difficulty crossing the cornea.

These data, combined with the relative specificity of MAGL for ocular monoacylglycerols and the lack of desensitization in MAGL-/- mice, suggest that the development of an optimized MAGL blocker offers therapeutic potential for treatment of elevated IOP.”

http://www.ncbi.nlm.nih.gov/pubmed/27333182

Fabp-1 gene ablation impacts brain endocannabinoid system in male mice.

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“Liver fatty acid binding protein (FABP1, L-FABP) has high affinity for and enhances uptake of arachidonic acid (ARA, C20:4, n-6) which, when esterified to phospholipids, is the requisite precursor for synthesis of endocannabinoids (EC) such as arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). The brain derives most of its ARA from plasma, taking up ARA and transporting it intracellularly via cytosolic fatty acid binding proteins (FABPs 3,5, and 7) localized within the brain. In contrast, the much more prevalent cytosolic FABP1 is not detectable in the brain but is instead highly expressed in the liver. Therefore, the possibility that FABP1 outside the central nervous system may regulate brain AEA and 2-AG was examined in wild-type (WT) and FABP1 null (LKO) male mice. LKO increased brain levels of AA-containing EC (AEA, 2-AG), correlating with increased free and total ARA in brain and serum. LKO also increased brain levels of non-ARA that contain potentiating endocannabinoids (EC*) such as OEA, PEA, 2-OG, and 2-PG. Concomitantly, LKO decreased serum total ARA-containing EC, but not non-ARA endocannabinoids. LKO did not elicit these changes in the brain EC and EC* due to compensatory upregulation of brain protein levels of enzymes in EC synthesis (NAPEPLD, DAGLα) or cytosolic EC chaperone proteins (FABPs 3, 5, 7, SCP-2, HSP70), or cannabinoid receptors (CB1, TRVP1). These data show for the first time that the non-CNS fatty acid binding protein FABP1 markedly affected brain levels of both ARA-containing endocannabinoids (AEA, 2-AG) as well as their non-ARA potentiating endocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/27167970

FABP1 in wonderland.

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“Cannabinoid receptors hold a core position in the brain and control memory, cognition, movement, and pain sensitivity. sn-2 arachidonoylglycerol (2-AG) activates neuronal cannabinoid receptors as a full agonist. The brain may rely on circulating arachidonic acid to synthesize endogenous cannabinoids. This Editorial highlights a study by Martin and coworkers in the current issue of the Journal of Neurochemistry in which the authors describe, for the first time, that liver acts as a pool of arachidonic acid that under certain conditions feeds the brain to produce endocannabinoids. Therapeutics affecting liver FABP1 levels should take into account that FABP1 represents a fatty acid reservoirs for the brain. Read the highlighted article “FABP-1 gene ablation impacts brain endocannabinoid system in male mice”” http://www.ncbi.nlm.nih.gov/pubmed/27329821