Fig. 1.

Schematic representation of various intracellular GPCRs. Left, proposed model of mGlu₅ receptors trafficking in neurons in which >90% of mGlu₅ traffics through the Golgi (27). Subsequently, 15–40% goes to the cell surface where it undergoes a cycle of constitutive endocytosis and recycling (27, 122). Alternatively, 60–85% of mGlu₅ is retrogradely trafficked back to the endoplasmic reticulum (ER) and then, via lateral diffusion (dotted blue line), reaches the nuclear membrane (27, 123). Middle, ligand bound F2rll can translocate from the retinal ganglion cell surface to the nucleus along microtubules (MTs); nuclear F2rl1 activates vascular endothelial growth factor (Vegfα) expression. In contrast, signaling from cell surface F2rl1 results in the angiogenic gene, Angl expression (16). Right, a growing number of GPCRs have been localized to the outer (MT₁, CB₁ receptors) and inner mitochondrial membranes (AT₂ receptor). Studies show that serotonin (5-HT) is converted into melatonin (MEL) within the mitochondrial matrix; MEL diffuses freely across membranes to activate MT₁ receptors in the outer mitochondrial membrane (52). CB₁ receptors have also been described in the outer mitochondrial membrane (124) although its downstream signaling machinery is primarily located within the matrix. The exact orientation of mitochondrial GPCRs and their signal transduction pathways is largely unknown. Other abbreviations include AC, adenylyl cyclase; sAC, soluble adenylyl cyclase; “I”, IP₃R, inositol trisphosphate receptors; DAG, diacylglycerol; PLC, phospholipase C; Complex I; “P”, phosphorylation site on Complex I; black arrows indicate enhancement of activity; black bars indicate reduction of activity; αi inhibitory subunit of Gi protein; N, amino terminus; and PKA, protein kinase A.