Rab11a and its binding partners regulate the recycling of the ß1-adrenergic receptor

• Published in: Cellular signalling 2011, Vol.23 (1), p.46-57
• Main Authors: Gardner, Lidia A., Hajjhussein, Hassan, Frederick-Dyer, Katherine C., Bahouth, Suleiman W.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Amino Acid Substitution; Biotinylation; Cell Line; Colocalization confocal microscopy; Endosomes - metabolism; Humans; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Isoproterenol - pharmacology; Lysosomes - metabolism; Mutagenesis, Site-Directed; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Myosin Type V - genetics; Myosin Type V - metabolism; rab GTP-Binding Proteins - metabolism; rab GTP-Binding Proteins - physiology; Rab proteins; rab4 GTP-Binding Proteins - metabolism; rab4 GTP-Binding Proteins - physiology; Receptors, Adrenergic, beta-1 - chemistry; Receptors, Adrenergic, beta-1 - genetics; Receptors, Adrenergic, beta-1 - metabolism; Recycling; RNA Interference; Vesicular Transport Proteins - metabolism; ß1-adrenergic receptors
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2010.07.020

ß1-adrenergic receptors (ß1-AR) are internalized in response to agonists and then recycle back for another round of signaling. The serine 312 to alanine mutant of the ß1-AR (S312A) is internalized but does not recycle. We determined that WT ß1-AR and S312A were internalized initially to an early sorting compartment because they colocalized by > 70% with the early endosomal markers rab5a and early endosomal antigen-1 (EEA1). Subsequently, the WT ß1-AR trafficked via rab4a-expressing sorting endosomes to recycling endosomes. In recycling endosomes WT ß1-AR were colocalized by > 70% with the rab11 GTPase. S312A did not colocalize with either rab4a or rab11, instead they exited from early endosomes to late endosomes/lysosomes in which they were degraded. Rab11a played a prominent role in recycling of the WT ß1-AR because dominant negative rab11a inhibited, while constitutively active rab11a accelerated the recycling of the ß1-AR. Next, we determined the effect of each of the rab11-interacting proteins on trafficking of the WT ß1-AR. The recycling of the ß1-AR was markedly inhibited when myosin Vb, FIP2, FIP3 and rabphillin were knocked down. These data indicate that rab11a and a select group of its binding partners play a prominent role in recycling of the human ß1-AR.