CB1 Cannabinoid Receptors and their Associated Proteins

Abstract

CB1 receptors are G-protein coupled receptors (GPCRs) abundant in neurons, in which they modulate neurotransmission. The CB1 receptor influence on memory and learning is well recognized, and disease states associated with CB1 receptors are observed in addiction disorders, motor dysfunction, schizophrenia, and in bipolar, depression, and anxiety disorders. Beyond the brain, CB1 receptors also function in liver and adipose tissues, vascular as well as cardiac tissue, reproductive tissues and bone. Signal transduction by CB1 receptors occurs through interaction with Gi/o proteins to inhibit adenylyl cyclase, activate mitogen-activated protein kinases (MAPK), inhibit voltage-gated Ca2+ channels, activate K+ currents (Kir), and influence Nitric Oxide (NO) signaling. CB1 receptors are observed in internal organelles as well as plasma membrane. β-Arrestins, adaptor protein AP-3, and G-protein receptor-associated sorting protein 1 (GASP1) modulate cellular trafficking. Cannabinoid Receptor Interacting Protein 1a (CRIP1a) is an accessory protein whose function has not been delineated. Factor Associated with Neutral sphingomyelinase (FAN) regulates ceramide signaling. Such diversity in cellular signaling and modulation by interacting proteins suggests that agonists and allosteric modulators could be developed to specifically regulate unique, cell type-specific responses.

Molecular Basis of Cannabinoid CB1 Receptor Coupling to the G Protein Heterotrimer Gαiβγ

“…CB1 exhibits modest basal activity in the absence of ligand, indicative of receptor-G protein coupling independent of agonist (20). Multiple chemical classes bind to the CB1 receptor and activate signal transduction pathways (21) in an agonist-specific manner (22). The molecular basis of CB1 receptor coupling to its cognate G protein is unknown.…”

Cannabinoids, the Heart of the Matter

“…In addition, CB1 receptors also function in the peripheral nervous system: in vascular and cardiac tissue, adipocytes, liver, GI tract and uterus to regulate basic physiological mechanisms such as energy balance and reproduction 48, 50, 51. The CB1 receptor also has influence on memory and learning behavior, plays a role in addiction processes, and mediation of the psychoactive effect of Tetrahydrocannabinol (THC) 52, 53. Signal transduction happens through the interaction with G proteins to inhibit adenylyl cyclase, activate mitogen‐activated protein kinases, inhibit voltage‐gated Ca 2+ channels, and activate K + currents; as well as to influence nitric oxide signaling 49, 53.…”

“…The CB1 receptor also has influence on memory and learning behavior, plays a role in addiction processes, and mediation of the psychoactive effect of Tetrahydrocannabinol (THC) 52, 53. Signal transduction happens through the interaction with G proteins to inhibit adenylyl cyclase, activate mitogen‐activated protein kinases, inhibit voltage‐gated Ca 2+ channels, and activate K + currents; as well as to influence nitric oxide signaling 49, 53. CB1 agonists include: ∆‐9‐THC, endogenous anandamide, 2‐AG, 2‐Arachidonoyl dopamine; and highly potent HU210, CP55940 and CP55244.…”

“…CB1 agonists include: ∆‐9‐THC, endogenous anandamide, 2‐AG, 2‐Arachidonoyl dopamine; and highly potent HU210, CP55940 and CP55244. Antagonists include: rimonabant, and structurally similar antagonists like AM241, taranabant, ACHSR, and AM4113 53. CB1 receptors can be co‐expressed with CB2 receptors.…”

Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids

“…CNR1 is coupled to the GNAI/ G i/o protein, and CNR1 activation inhibits the ADCY/adenylyl cyclase activity and cyclic adenosine monophosphate (cAMP) production, while activating the mitogen-activated protein kinase (MAPK) pathways, including MAP2K1 (mitogen-activated protein kinase 1)/MEK1-MAP2K2/MEK2 and MAPK8/ JNK1-MAPK9/JNK2 cascades. 7,19 Thus, we measured cannabinoid-induced cAMP suppression (Fig. 2C) and MAPK cascade phosphorylation (Fig.…”