Figure 3.

Extra- and intracellular GPCR activation by endogenous ligands. GPCRs are represented as orange proteins whose carboxyl groups are shown as gray dots whereas their N-terminal groups are differently shaped symbols of different colors. Canonically, ligands activate GPCRs at the plasma levels (“1”) where they promote internalization as shown for oxytocin receptors (OXTR). Internalized receptors are recycled (“2”) and their ligand degraded in lysosomes (“3”) or translocated in complex with their ligand to the outer and inner nuclear membrane (“4”). Some GPCRs embedded in the inner nuclear membrane are activated by hydrophilic ligands that cross the plasma membrane through transporters (organic cation transporter 3, OCT3) such as noradrenaline (NA) that activates the nuclear compartmentalized adrenergic receptors (“5”). Additionally, highly lipophilic ligands such as anandamide (AEA) cross the plasma membrane through transporters (EMT) and reach the cannabinoid receptors on the outer mitochondrial membrane through intracellular carriers, regulating cell respiration (“6”). Some ligands such as melatonin reach their intracellular GPCR targets by crossing the plasma membrane through simple diffusion and by an “automitocrine” mechanism in which the intracellular organelle itself synthesizes the ligand, autoregulating its own functions (“7”, “8”, respectively).