The fate of the internalized apelin receptor is determined by different isoforms of apelin mediating differential interaction with beta-arrestin.
Internalization of the apelin receptor by apelin-13 is characterized by dissociation from beta-arrestins and rapid recycling to the cell surface. Paradoxically, the apelin receptor internalized by apelin-36 was sequestered intracellularly. The specific pathways involved in apelin receptor trafficking were resolved using beta-arrestin1 and constitutively active and dominant negative Rab proteins following activation by apelin-13 or apelin-36. beta-Arrestin1 dissociated from the apelin-13-internalized receptor while the apelin-36-internalized receptor was trafficked with beta-arrestin1 to intracellular compartments. The apelin-13-internalized receptor was rapidly recycled to the cell surface through a Rab4-dependent mechanism while Rab7 targeted the receptor to lysosomes. The internalized receptor co-expressed with dominant negative Rab4 were trafficked to lysosomes. These observations revealed a novel ligand-dependent targeting of the apelin receptor to beta-arrestin-associated and -dissociated trafficking pathways and a role for different Rab proteins to direct these pathways.
Lee
Dennis K
DK
Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Ferguson
Stephen S G
SS
George
Susan R
SR
O'Dowd
Brian F
BF
D000073861:Apelin; D000075244:Apelin Receptors; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000071557:beta-Arrestins; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
C115436:APLN protein, human; C104575:APLNR protein, human; D000073861:Apelin; D000075244:Apelin Receptors; D019390:Arrestins; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; C495199:apelin-13 peptide; D000071557:beta-Arrestins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D020691:rab GTP-Binding Proteins; D020695:rab4 GTP-Binding Proteins