Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors

Bauer, Mark D.; Chicca, Andrea; Tamborrini, Marco; Eisen, David; Lerner, Robert G.; Lutz, Beat; Poetz, Oliver; Pluschke, Gerd; Gertsch, Jürg

doi:10.1074/jbc.m112.382481

Cited by 154 publications

(182 citation statements)

References 68 publications

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“…Figure 4D shows the effects of pepcan-12, a 12-amino-acid neuropeptide that is highly expressed in mouse brain (Gomes et al, 2009), on the binding of the orthosteric radioligand agonist [ 3 H]WIN55212-2 at the cannabinoid CB 1 receptor. In contrast to the complete inhibition of radioligand binding mediated by the orthosteric agonist CP55,940, pepcan-12 only partially inhibited specific radioligand binding at saturating concentrations, consistent with limited negative cooperativity (Bauer et al, 2012). This negative allosteric effect on CB 1 agonist affinity is also manifested in functional studies of receptor signaling (Bauer et al, 2012).…”

Section: Amino Acids and Peptides As Allosteric Modulatorsmentioning

confidence: 88%

“…In contrast to the complete inhibition of radioligand binding mediated by the orthosteric agonist CP55,940, pepcan-12 only partially inhibited specific radioligand binding at saturating concentrations, consistent with limited negative cooperativity (Bauer et al, 2012). This negative allosteric effect on CB 1 agonist affinity is also manifested in functional studies of receptor signaling (Bauer et al, 2012). Negative allosteric modulation of the CB 1 receptor may have beneficial effects in pathologic states, such as obesity and type 2 diabetes, while avoiding on-target depression-related side effects often attributed to classic CB 1 antagonists (de Kloet and Woods, 2009).…”

Section: Amino Acids and Peptides As Allosteric Modulatorsmentioning

confidence: 94%

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Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Westhuizen

Valant

Sexton

et al. 2015

J Pharmacol Exp Ther

131

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Section: Amino Acids and Peptides As Allosteric Modulatorsmentioning

confidence: 88%

Section: Amino Acids and Peptides As Allosteric Modulatorsmentioning

confidence: 94%

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Westhuizen

Valant

Sexton

et al. 2015

J Pharmacol Exp Ther

131

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“…Another endogenous allosteric modulator of the CaSR is the g-glutamyl-peptide glutathione (Broadhead et al, 2011), whereas the tetrapeptide "5HT-moduline" (Leu-Ser-Ala-Leu) has been proposed as an endogenous modulator of the 5HT 1B receptor in the central nervous system Massot et al, 1996;Rousselle et al, 1996). More recently, studies in mouse and hamster brain tissues identified a family of peptides, known as the pepcans, that have been proposed as endogenous allosteric modulators of the cannabinoid CB 1 receptor (Bauer et al, 2012).…”

Section: Endogenous Allosteric Modulatorsmentioning

confidence: 99%

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

2014

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It is now widely accepted that G protein-coupled receptors (GPCRs) are highly dynamic proteins that adopt multiple active states linked to distinct functional outcomes. Furthermore, these states can be differentially stabilized not only by orthosteric ligands but also by allosteric ligands acting at spatially distinct binding sites. The key pharmacologic characteristics of GPCR allostery include improved selectivity due to either greater sequence divergence between receptor subtypes and/or subtype-selective cooperativity, a ceiling level to the effect, probe dependence (whereby the magnitude and direction of the allosteric effect change with the nature of the interacting ligands), and the potential for biased signaling.Recent chemical biology developments are beginning to demonstrate how the incorporation of analytical pharmacology and operational modeling into the experimental workflow can enrich structure-activity studies of allostery and bias, and have also led to the discovery of a new class of hybrid orthosteric/ allosteric (bitopic) molecules. The potential for endogenous allosteric modulators to play a role in physiology and disease remains to be fully appreciated but will likely represent an important area for future studies. Finally, breakthroughs in structural and computational biology are beginning to unravel the mechanistic basis of GPCR allosteric modulation at the molecular level.

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“…These latter compounds are particularly intriguing because they potentiate agonist binding to the CB 1 R, at the same time inhibiting agonist activity in numerous functional assays (Price et al, 2005;Horswill et al, 2007). Other endogenous ligands, including pregnenolone, pepcans, and lipoxin A4, may also act allosterically at CB 1 Rs, as was recently suggested (Bauer et al, 2012;Pamplona et al, 2012;Vallee et al, 2014). However, further studies are required to validate these putative allosteric effects.…”

mentioning

confidence: 98%

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

et al. 2015

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CB 1 cannabinoid receptors (CB 1 Rs) are attractive therapeutic targets for numerous central nervous system disorders. However, clinical application of cannabinoid ligands has been hampered owing to their adverse on-target effects. Ligand-biased signaling from, and allosteric modulation of, CB 1 Rs offer pharmacological approaches that may enable the development of improved CB 1 R drugs, through modulation of only therapeutically desirable CB 1 R signaling pathways. There is growing evidence that CB 1 Rs are subject to ligand-biased signaling and allosterism. Therefore, in the present study, we quantified ligand-biased signaling and allosteric modulation at CB 1 Rs. Cannabinoid agonists displayed distinct biased signaling profiles at CB 1 Rs. For instance, whereas 2-arachidonylglycerol and WIN55,212-2 [(R)- (1) [5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide] displayed biased allosteric effects by blocking cAMP inhibition mediated by all cannabinoid ligands tested, at the same time having little or no effect on ERK1/2 phosphorylation mediated by a subset of these ligands. Org27569 also displayed negative binding cooperativity with [however, it had minimal effects on binding of cannabinoid agonists. Furthermore, we highlight the need to validate the reported allosteric effects of the endogenous ligands lipoxin A4 and pregnenolone at CB 1 Rs. Pregnenolone but not lipoxin A4 displaced [ 3 H]SR141716A, but there was no functional interaction between either of these ligands and cannabinoid agonists. This study demonstrates an approach to validating and quantifying ligand-biased signaling and allosteric modulation at CB 1 Rs, revealing ligand-biased "fingerprints" that may ultimately allow the development of improved CB 1 R-targeted therapies.

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Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors

Cited by 154 publications

References 68 publications

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor

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Identification and Quantification of a New Family of Peptide Endocannabinoids (Pepcans) Showing Negative Allosteric Modulation at CB1 Receptors

Cited by 154 publications

References 68 publications

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Endogenous Allosteric Modulators of G Protein–Coupled Receptors

Advances in G Protein-Coupled Receptor Allostery: From Function to Structure

Biased Agonism and Biased Allosteric Modulation at the CB1Cannabinoid Receptor

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Product

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Biased Agonism and Biased Allosteric Modulation at the CB₁Cannabinoid Receptor