A real time screening assay for cannabinoid CB1 receptor-mediated signaling

Andersen, Haley K.; Piroli, Gerardo G.; Walsh, Kenneth B.

doi:10.1016/j.vascn.2018.05.001

Cited by 10 publications

(17 citation statements)

References 33 publications

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“…7 | GIRK MEDIATED EFFECTS OF Δ 9 -THC AND OTHER CB 1 R AGONISTS Andersen, Piroli and Walsh (2018) showed that both WIN and Δ 9 -THC activate GIRKs at different efficacies in a mouse pituitary cell line. The CB 1 R agonists WIN and (À)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl) phenyl]trans-4-(3-hydroxypropyl) cyclohexanol (CP) can alter the K + currents through GIRK channels in xenopus oocytes.…”

Section: δ 9 -Thc and Other Cb 1 R Agonists Can Modulate The Nmdarmentioning

confidence: 99%

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Niknam

Iyer

Campbell

et al. 2022

Birth Defects Research

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This review summarizes the most common potential pathways of neurodevelopmental toxicity due to perinatal exposure to Δ9‐tetrahydrocannabinol (Δ9‐THC) that lead to behavioral and other adverse outcomes (AOs). This is Part III in a set of reviews highlighting the animal‐derived data considered by California's Developmental and Reproductive Toxicant Identification Committee (DARTIC) in 2019. The Hazard Identification Document (HID) provided to the DARTIC included a summary of human, whole animal, and mechanistic data on the neurodevelopmental toxicity of cannabis smoke and Δ9‐THC. The literature search for mechanistic data has been updated through 2020. We focus on mechanistic pathways relating to behavioral and other neurodevelopmental outcomes of perinatal exposure to Δ9‐THC. The endocannabinoid system (EC system) plays a crucial role in many processes involved in neurodevelopment and exposure to Δ9‐THC can alter these processes. Whole animal studies report changes in cognitive ability, behavior, and motor function after prenatal exposure to Δ9‐THC. Findings from mechanistic studies add to this evidence and further provide information regarding the pathways leading to these outcomes. Neuromechanistic studies can bridge the gaps between molecular initiating events and apical neurodevelopmental endpoints caused by a chemical. They offer insight into potential alterations in the same pathways by other chemicals that can also result in AOs. Studies of cannabinoid receptor agonist‐induced molecular alterations and provide deep biological plausibility at the mechanistic level for the cognitive, behavioral, and motor impairments observed in animal studies after perinatal exposure to Δ9‐THC.

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Section: δ 9 -Thc and Other Cb 1 R Agonists Can Modulate The Nmdarmentioning

confidence: 99%

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Niknam

Iyer

Campbell

et al. 2022

Birth Defects Research

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“…75 In addition to screening Kir3.1/ Kir3.2 channels, MPSD assay systems have been utilized in AtT20 and HEK293 cells to examine the efficacy of GPCR ligands such as somatostatin, opioids, and cannabinoids in activating GIRK channels. [76][77][78] While fluorescent MPSDs provide a convenient and inexpensive approach for measuring changes in membrane potential, they represent an indirect measure of Kir channel activity. This method contrasts with ion flux analysis and patch clamp measurements that directly measure channel flux or current (see below).…”

Section: Fluorescent Mpsd Assaysmentioning

confidence: 99%

Section: Screening Technologies For Kir Channelsmentioning

confidence: 99%

Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

Walsh

2020

SLAS Discovery

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“…Gi/o(βγ) inhibits the opening of Ca 2+ channels (N & P/Q type) and opens G protein-coupled inward rectifier K + (GIRK) channels [ 12 ]. The GIRK channels are composed of four mammalian subunits, GIRK1 (Kir3.1), GIRK2 (Kir3.2), GIRK3 (Kir3.3), and GIRK 4 (Kir3.4), and are members of a family of inward rectifier K + (Kir) channels [ 14 , 15 ]. GIRK1-3 are predominant subunits in the brain with overlapping but distinct expression patterns throughout the CNS and peripheral nervous system that form heterotetrameric channels [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported to enhance Gi/o (α) and Gi/o(βγ) signaling after binding to CB1 in the mouse STHdh(Q7/Q7) cell culture model of striatal medium spiny projection neurons that endogenously express CB1 [ 24 ]. Additionally, the application of WIN55,212-2 to AtT20 pituitary cells expressing CB1 activated GIRK currents [ 15 ]. In a Xenopus oocyte system co-expressing CB1 and GIRK1/4, WIN55,212-2 enhanced currents carried by GIRK1/4 through activating CB1 [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Peigneur

Tytgat

2021

Biomedicines

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The coupling of cannabinoid receptors, CB1 and CB2, to G protein-coupled inward rectifier potassium channels, GIRK1 and GIRK2, modulates neuronal excitability in the human brain. The present study established and validated the functional expression in a Xenopus laevis oocyte expression system of CB1 and CB2 receptors, interacting with heteromeric GIRK1/2 channels and a regulator of G protein signaling, RGS4. This ex vivo system enables the discovery of a wide range of ligands interacting orthosterically or allosterically with CB1 and/or CB2 receptors. WIN55,212-2, a non-selective agonist of CB1 and CB2, was used to explore the CB1- or CB2- GIRK1/2-RGS4 signaling cascade. We show that WIN55,212-2 activates CB1 and CB2 at low concentrations whereas at higher concentrations it exerts a direct block of GIRK1/2. This illustrates a dual modulatory function, a feature not described before, which helps to explain the adverse effects induced by WIN55,212-2 in vivo. When comparing the effects with other typical cannabinoids such as Δ9-THC, CBD, CP55,940, and rimonabant, only WIN55,212-2 can significantly block GIRK1/2. Interestingly, the inward rectifier potassium channel, IRK1, a non-G protein-coupled potassium channel important for setting the resting membrane voltage and highly similar to GIRK1 and GIRK2, is not sensitive to WIN55,212-2, Δ9-THC, CBD, CP55,940, or rimonabant. From this, it is concluded that WIN55,212-2 selectively blocks GIRK1/2.

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A real time screening assay for cannabinoid CB1 receptor-mediated signaling

Cited by 10 publications

References 33 publications

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

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A real time screening assay for cannabinoid CB1 receptor-mediated signaling

Cited by 10 publications

References 33 publications

Animal evidence considered in determination of cannabis smoke and Δ9‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Animal evidence considered in determination of cannabis smoke and Δ9‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators

WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels

Contact Info

Product

Resources

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Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action

Animal evidence considered in determination of cannabis smoke and Δ⁹‐tetrahydrocannabinol as causing reproductive toxicity (developmental endpoint): Part III. Proposed neurodevelopmental mechanisms of action