Figure 4.

Compartmentalized GPCRs as novel pharmacological targets. The endogenous ligand anandamide (AEA) after uptake by the endocannabinoid membrane transporter (EMT) interacts with cytosolic proteins such as albumin, HSP70, FABP5 and is degraded by fatty acid amide hydrolase and monoacylglycerol lipase enzymes (EDE). These steps can be pharmacologically targeted to decrease (guineensine, “1”; BMS309403, “2”) or increase (LY2183240, “3”) the intracellular levels of AEA, modulating its compartmentalized intracellular signaling effects. Intracellular GPCR signaling is also blocked by conjugation of receptor-specific antagonists. NK1R is depicted as a seven-transmembrane orange protein, whose gray dots represent carboxyl groups, and the N-terminal group is a blue symbol. Antagonists of neurokinin type 1 (NK1) and spantide (SPT), when conjugated with polyethylene glycol (PEG) and cholestanol (CHO), inhibit signals that originate from endosomal NK1 receptors emphasizing the physiological importance of GPCR signaling from endosomes (“4”).