Endocannabinoids + Rs

Question 1

Which are the endogeneus agonists of the cannabinoid receptors?

Answer 1

2-acylglycerol (2-AG) and anandamide (AEA)

Question 2

How is 2-AG synthesized?

Answer 2

PIP2 is cleaved into IP3 and DAG by phospholipase C, then DAG is converted into 2-AG by diacylglycerol lipase (DAGL), which is Ca^2+ activated.

Question 3

How is 2-AG degraded?

Answer 3

2-AG is degraded by the enzyme monoacylglycerol lipase (MAGL) into a fatty acid (arachidonic acid (AA)) and glycerol.

Question 4

Describe the struture of 2-AG.

Answer 4

Composed of a fatty acid chain and glycerol.

Question 5

How is AEA degraded?

Answer 5

AEA is degraded by the enzyme fatty acid amide hydrolase (FAAH) into a fatty acid (arachidonic acid (AA)) and an ethanolamine.

Question 6

What are the plant alkaloid agonists of the CB Rs?

Answer 6

Tetrahydrocannabinol (THC) and cannabidiol (CBD)

Question 7

Describe the CB Rs.

Answer 7

The cannabinoid receptors are two GPCRs, CB1 R and CB2 R. They are both Gi coupled. CB1 R mainly occurs in the brain, and CB2 R mainly occurs in the periphery. They are often found on pre-synaptic neurons.

Question 8

What is a 2-AG signalosome?

Answer 8

A complex of mGluR5, DAGL and PLC sitting close together in the PM. Glu stimulates the Gq to activate the PLC, that cleaves PIP2 to IP3 and DAG (IP3 gates Ca^2+ channel on ER, Ca^2+ activates DAGL). DAGL then converts DAG to 2-AG, which is then released to inhibit the pre-synaptic neuron.

Question 9

Describe how 2-AG may be involved in euphoria.

Answer 9

CB1 R are present on the GABAergic neurons in the ventral tegmental area (VTA) of the brain. When 2-AG binds to CB1 R the GABAergic neuron is inhibited, meaning it cannot inhibit the dopaminergic neurons in VTA, resulting in more dopamine in the nucleus accumbens (the reward center of the brain) = euphorid. CB1-R are also present on the glutamatergic neurons in the VTA, which stimulate the GABAergic neurons (inhibition of these also results in more dopamine in nucleus accumbens = euphoria)

Question 10

Explain some of the functions of CB1 - and CB2 R.

Answer 10

Blocking of pain and memory, relief of depression and anxiety, stimulation of hunger and sleepiness and decression of inflammation and neuroinflammation,