5 - Cannabinoids Flashcards
What is cannabidiol (CBD)?
A weak agonist for CB1 and CB2 cannabinoid receptors
May be a good substitute for THC in medical purposes. Less psychoactive effects.
True or false. The density of CB1 cannabinoid receptors in the brain is really high
True
Less CB2, found in peripheral immune system and on glia in the brain
What are the two endogenous cannabinoid? What is the first an agonist of (in addition to cannabinoid receptors)
Anandamide
- Also an agonist of TRPV1 (capsaicin) channel
2-arachidonoylglycerol (2-AG)
There are more, such as 2-AG ether and N-arachidonoyl dopamine, but they aren’t as important to know..
What does CB1 cannabinoid receptor activation do?
- Cell transport
- Synaptic plasticity
- Modulates ion channels and a variety of G protein-coupled receptors
What does activation of CB1 cannabinoid receptors do?
Triggers an anti-inflammatory response through inhibition of microglia and inhibiting their release of inflammatory cytokines.
What is synthesis of endogenous cannabinoids dependent on?
Phospholipids and phospholipase C and phospholipase A2
How is human reaction to cannabinoids different from rodents?
Rodents don’t show much pleasure, just anxiety. Can’t make a good model for self-administered stimulation.
CB1 receptor increases food intake ‘primarily’ through what type of cell?
Melanin concentrating hormone expressing neurons
- Increase excitability by decreasing GABA inhibition
CB1 does this through other pathways as well
What are the two main preparations derived from cannabis?
- Marijuana
- Hashish
Who discovered the analgesic, appetite stimulant, antiemetic, muscle relaxant and anticonvulsant properties of cannabis?
William O’Shaughnessy, British Physician
What are the three major psychoactive compounds of cannabis?
- Δ9- tetrahydrocannabinol (THC)
- Δ8- tetrahydrocannabinol
- Cannabidiol (CBD)
What type of receptors are cannabinoid receptors?
G protein-coupled receptors
Where is the CB1 cannabinoid receptor subtype most commonly found? CB2?
The CB1 cannabinoid receptor subtype is found predominantly on neurons in the central nervous system. They are found throughout the brain but are most densely concentrated in the basal ganglia, hippocampus and cerebellum.
The CB2 cannabinoid receptor subtype is present in the immune system in the periphery but also in the brain in the glia.
What is the receptor encoded by GPR55 gene?
The receptor encoded by GPR55 gene is also responding to endogenous cannabinoids. The presence of another putative cannabinoid receptor CB3 was suggested in hippocampus.
What is anandamide?
The endogenous cannabinoid anandamide is also an agonist of TRPV1 (capsaicin) channel.
Describe cannabinoids and glycine
It was recently found that cannabinoids enhance function of glycine receptor. The cannabinoid-induced analgesia is absent in mice lacking α3GlyRs but not in those lacking CB1 and CB2 receptors.
Cannabinoids acting via CB1 inhibit _____ ______ and also inhibit ____, ___ and ___ channels.
Cannabinoids acting via CB1 inhibit adenylyl cyclase and also inhibit L, N- and P/ Q-type voltage-sensitive Ca2+ channels.
Describe CB receptor signalling (4)
- Cannabinoids acting via CB1 inhibit adenylyl cyclase and also inhibit L, N- and P/ Q-type voltage-sensitive Ca2+ channels.
- Reduction of PKA activity is related to a reduction of gene expression through decreasing cAMP response element (CRE) activity.
- CB1 receptor activation can also stimulate several intracellular kinases, such as focal adhesion kinase (FAK), phosphatidyl inositol-3-kinase (PI3-K) and its downstream effectors protein kinase B (PKB) (also known as AKT) and Raf-1, extracellular signal-
regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated kinase. - CB1 receptor activation can also lead to increased expression levels of calcineurin, also called protein phosphatase 2B. Stimulation of cytoplasmic kinases can also mediate CB1 receptor- induced expression of immediate early genes (IEG).
Which kinases can CB1 stimulate? (5)
- Focal adhesion kinase (FAK),
- Phosphatidyl inositol-3-kinase (PI3-K) and its downstream effectors: protein kinase B (PKB) (also known as AKT) Raf-1,
- extracellular signal-
regulated kinases (ERKs), - c-Jun N-terminal kinase (JNK)
- p38 mitogen-activated kinase.
- It was shown that CB1 cannabinoid receptors also leads to activation or Gs and Gq proteins. In addition the CB1 cannabinoid receptor also signals trough non-G protein partners such as the adaptor protein FAN. Preferential activation of different intracellular effectors by each G protein contributes to diversity and selectivity of responses regulated by cannabinoid receptors
List 5 signalling cascades induced by CB1 activation
- cAMP/PKA MAPK
- Calcium/potassium currents
- cAMP/PKA calcium currents
- Intracellular calcium release
- Transient MAPK
It was shown that CB1 cannabinoid receptors also leads to activation or Gs and Gq proteins. In addition the CB1 cannabinoid receptor also signals trough non-G protein partners such as the adaptor protein FAN. Preferential activation of different intracellular effectors by each G protein contributes to diversity and selectivity of responses regulated by cannabinoid receptors
List 6 anti-inflammatory effects of cannabinoids
- Microglia inhibition
- Reduction of pro-inflammatory cytokines released from microglia
- CB1/CB2 agonists inhibit glutamate release from synapto- somes
- Inhibits glutamatergic transmission
- CB1 receptor activation also inhibits cell death by reduction of the NMDA-mediated release of Ca2+ from intracellular
stores and and ROS release - Cannabinoids also stimulate intracellular Ca2+ uptake into mitochondrial sinks
What are endogenous cannabinoids derived from and what class do they belong to?
Derived from arachidonic acid
Belong to class of bioactive eicosanoids
Describe the two endogenous cannabinoid’s synthesis and degradation
Synthetic pathways to endogenous cannabinoids can be regulated by G protein- coupled receptors. - Anandamide and 2-AG are synthesized from membrane phospholipids.
- Anandamide is degraded by fatty acid amide hydrolase (FAAH)
- 2-AG is synthesized by monoacylglycerol lipase (MAGL).
How do CB1 receptors control cell fate? (6)
- Cannabinoids modulate sphingolipid metabolising pathways by inducing sphingomyelin (SM) breakdown and by increasing the levels of the second messenger ceramide.
- Ceramide may then induce extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase and p38 mitogen-activated protein kinase.
- The activation of ERK cascade is known to induce cell proliferation but in
some situations ERK mediates growth arrest, as well as cell death. - Cannabinoids induce generation of ceramide (“tumor suppressor lipid”) by inducing the adaptor protein FAN. There are evidences that cannabinoid- induced ceramide production triggers apoptosis in cancer cells in vitro (C6 glioma and PC-12 pheochromocytoma cells).
- CB1 receptor modulation of ion channels, inducing inhibition of N- and P/Q- type voltage-sensitive Ca2+ channels and activation of rectifying K+ channels could be responsible for the inhibition of the release of glutamate and other neurotransmitters by affecting membrane depolarization and exocytosis.
- Not all cannabinoids effects are “beneficial”. THC was shown to have neurotoxic effects. After chronic THC oral administration there were observed, morphological changes in the hippocampus - decreases in the mean volume, synaptic density, and dendritic length of CA3 pyramidal neurons. This effect could result from CB1-mediated apoptosis, and might involve a phospholipase A2-induced release of arachidonic acid, which promotes the activation of cyclooxygenases and lipoxygenases. Both pathways generate free radicals that can lead to lipid peroxidation and cell death.
