Question

The delta-9-tetrahydrocannabinol(THC) interaction with Cannabinoid type 1 receptor (CB1R) follows the beta-arrestin pathways for signaling and desensitization. Describe the signaling pathway/s for CB1R starting from the THC binding. Your answer should include, and define, the following terms. Adenylyl cyclase, c-AMP, protein kinase B (Akt) , protien kinase A (PKA), inhibition, beta -arrestin, GRK, and desensitization.

Answer 1

1. CB1 Receptor is a GPCR receptor with Gi/o protein. When THC ligand binds to CB1 Receptor, the Gi/o protein inhibits the activity of adenylyl cyclase (AC) thus inhibiting the production of cAMP from ATP. cAMP normally activates Protein Kinase A. Under the circumstances of reduced supply of cAMP, Protein Kinase A is inhibited. Thus the activation of downstream elements is inhibited.

2. CB1 Receptor is able to suppress the Voltage Gated Calcium Channel thus inhibiting the influx of calcium ions.

3.In addition, the CB1 Receptor activates mitogen activated protein kinases (MAPKs) inclucing ERK1/2, p38,etc .

4. CB1 Receptor also acts through PI3 - Kinase B (Akt) pathway. This leads to activation of protein production mechanisms. CB1 Receptor activates the PI-3 Kinase which catalyzes the formation of PI - 3,4,5 - triphosphate. Protein Kinase B binds to PI - 3,4,5 - triphosphate. PKB then phosphorylates many downstream regulatory elements.

Receptor Desensitization :

Ligand binding of CB1 Receptor results in phosphorylation of CB1 Receptors by G - Receptor Kinases. Phosphorylation of G protein stimulates the binding of beta-arrestin to the receptors and receptor internalization. Beta- arrestin bind through their serine and threonine amino acids in the extreme carboxyl terminal.