Regulation of Calcium Oscillations in β-Cells by Co-activated Cannabinoid Receptors

Laguerre, Aurélien; Keutler, Kaya; Hauke, Sebastian; Schultz, Carsten

doi:10.1016/j.chembiol.2020.10.006

Cited by 15 publications

(7 citation statements)

References 72 publications

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“…TRPV1 is a Ca 2+ channel and eCBS receptors are known to trigger Ca 2+ flux ( 15 , 16 ). Therefore, as the next step we tested the effect of the three cannabinoids on cytosolic Ca 2+ levels.…”

Section: Resultsmentioning

confidence: 99%

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Cannabinoid Combination TargetsNOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Besser,

Gelfand,

Procaccia

et al. 2023

Preprint

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In T-cell acute lymphoblastic leukemia (T-ALL) more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, Cannabidiol (CBD) and Cannabidivarin (CBDV); whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through Cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca2+. This is followed by increased mRNA and protein expression of ATF4, CHOP and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in-vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treatingNOTCH1-mutated diseases and cancers such as T-ALL.

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Section: Resultsmentioning

confidence: 99%

“…Notable eCBS receptors include cannabinoid receptor type 1 (CB1) and CB2, which belong to the family of G protein-coupled receptors, and transient receptor potential vanilloid type 1 (TRPV1), which is an ion channel (13). The eCBS participates in many physiological activities, including the regulation of Ca 2+ homeostasis (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoid Combination TargetsNOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Besser,

Gelfand,

Procaccia

et al. 2023

Preprint

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“…While similar results could also be achieved using other specialized photocages 18,19 , future applications of our approach with alternative SNAP-tag targeting sequences will allow us to direct FAA signalling to a variety of subcellular locations without requiring the synthesis of new compounds. Moreover, an increasing body of work indicates that CBRs can be found on internal membranes, even in -cells 7,41 . Thus, applying OCTligands to target organelles such as mitochondria or the endoplasmic reticulum will allow us to investigate the function of intracellular receptor pools.…”

Section: Chemical Science Accepted Manuscriptmentioning

confidence: 99%

“…The frequency and amplitude of these oscillations correlate tightly to insulin secretion 5 . Notably, β-cells express multiple cannabinoidsensitive receptors and channels that affect β-cell excitability and GSIS 6,7 , including CB1, CB2, transient receptor potential cation channel subfamily V member 1 (TRPV1) 8 , peroxisome proliferator-activated receptors 9 and the atypical cannabinoid receptor GPR55 6,10,11 , which is a stimulatory GPCR. In contrast to the inhibitory CB1 and CB2 receptors, GPR55 activation increases [Ca 2+ ] i via Gα q/11 and phospholipase C (PLC) 12 .…”

Section: Introductionmentioning

confidence: 99%

Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells

et al. 2021

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“…30 We and others have shown that CB1 and CB2 receptors have counteracting effects on insulin secretion. 31,32,33 By using a photo-activatable (caged) 2-AG, 34 we demonstrated that CB1 and CB2 were activated by the endocannabinoid in a concerted manner that regulated intracellular [Ca 2+ ]i levels. 31 We further showed that while CB1 activation was required to maintain intracellular [Ca 2+ ]i oscillations, CB2 activation had a dampening role.…”

mentioning

confidence: 95%

Incorporation of unnatural amino acid for the tagging of cannabinoid receptors 1 and 2 reveals receptor roles in regulating cAMP levels

Thomas

Schultz

Laguerre

2021

Preprint

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The role of CB1/CB2 co-expression in cell signaling remains elusive. We established a simplified mammalian cell model system in which expression of CB1 or CB2 can be easily monitored under a confocal microscope. For this, we applied amber codon suppression in live cells to incorporate a single trans-cyclooctene (TCO) bearing amino acid in one of the extracellular loops of CB1 or CB2, followed by fluorescent labeling via click chemistry. We employed genetically encoded biosensors to measure the roles of CB1 and/or CB2 in regulating intracellular calcium ([Ca2+]i) and cAMP ([cAMP]i) levels. We show that the agonist-mediated activation of tagged-CB1 or -CB2 can transiently elevate [Ca2+]i levels. However, when the two receptors were co-expressed in the same cell, CB2 no longer signaled through calcium although CB1-mediated transient elevation of [Ca2+]i levels was unaffected. Because of the existence of crosstalk between calcium and cAMP signaling, we measured the effects of CB1 and/or CB2 in regulating adenylate cyclase activity. We found that the expression of CB1 increased forskolin-induced [cAMP]i levels compared to non-transfected cells. Conversely, CB2 expression decreased stimulated [cAMP]i levels under the same conditions. Finally, co-expressed CB1 and CB2 receptors showed additive yet opposing effects on stimulated [cAMP]i levels. These observations suggest that co-expressed CB1/CB2 act locally as a pair in regulating cell excitability by modulating stimulated [cAMP]i levels.

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Regulation of Calcium Oscillations in β-Cells by Co-activated Cannabinoid Receptors

Cited by 15 publications

References 72 publications

Cannabinoid Combination TargetsNOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Cannabinoid Combination TargetsNOTCH1-Mutated T-ALL Through the Integrated Stress Response Pathway

Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells

Incorporation of unnatural amino acid for the tagging of cannabinoid receptors 1 and 2 reveals receptor roles in regulating cAMP levels

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