9.A.14.2.2
Cannabinoid receptor 1, CB1 or CB-R, of 472 aas and 7 TMSs. The endocannabinoid system is widely present in the retina where it can modulate neurotransmitter release and ion channel activity (Bouchard et al. 2016). Endogenous endocannabinoids such as anandamide and 2-arachidonoyl glycerol (2AG) bind to the receptor and influence many processes including feeding, learning, memory, pain, emotions, sleep and dreams (Murillo-Rodriguez et al. 2017). Membrane lipids are integral parts of transmembrane allosteric sites in GPCRs as has been established with the cannabinoid CB1 receptor bound to a negative allosteric modulator, ORG27569, and analogs (Obi and Natesan 2022).  All-atom molecular dynamics simulations have indicated the involvement of a conserved polar signaling channel in the activation mechanism of the type I cannabinoid receptor (Sarkar et al. 2023). In earlier studies of the mu-opioid and beta(2)-adrenergic receptors (MOP and beta(2)AR, respectively) these authors found that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This suggested that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Sarkar et al. 2023 examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if the previous assumptions could be applied to the CB1 receptor. In addition to the identification of the previously proposed general features of the activation mechanism, several specific properties of CB1 were indicated that could be associated with the signaling profile of this receptor (Sarkar et al. 2023).