title: Rab11a and myosin Vb regulate recycling of the M4 muscarinic acetylcholine receptor.
abstract: Agonist-induced internalization followed by subsequent return to the cell surface regulates G-protein-coupled receptor (GPCR) activity. Because the cellular responsiveness to ligand depends on the balance between receptor degradation and recycling, it is crucial to identify the molecules involved in GPCR recovery to the cell surface. In this study, we identify mechanisms involved in the recycling of the M4 subtype of muscarinic acetylcholine receptor. M4 is highly expressed in the CNS, plays a role in locomotor activity, and is a novel therapeutic target for neurologic and psychiatric disorders. Previous studies show that, after cholinergic stimulation, M4 internalizes from the cell surface to endosomes in cell culture and the rat brain. Here, we show that, after activation, M4 traffics to transferrin receptor- and Rab11a-positive perinuclear endosomes. Expression of the constitutively GDP-bound, inactive mutant Rab11aS25N inhibits M4 trafficking to recycling endosomes. Expression of the C-terminal tail of myosin Vb, a Rab11a effector, enhances M4 accumulation in perinuclear endosomes. Both Rab11aS25N and the myosin Vb tail impair M4 recycling. The results demonstrate that GPCR recycling is mediated through a discrete pathway using both Rab11a and myosin Vb.
authors.affiliation: Center for Neurodegenerative Disease and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Volpicelli
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Guofu
authors.initials: G
authors.lastname: Fang
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
mesh_terms: D000818:Animals; D002451:Cell Compartmentation / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D007150:Immunohistochemistry; D018721:Muscarinic Agonists / Q000494:pharmacology; D009218:Myosins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D035361:Transcription Factor TFIIIB; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000099193:rab11 GTP-Binding Proteins
chemical_list: D018721:Muscarinic Agonists; D009218:Myosins; D009687:Nuclear Proteins; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D000254:Sodium-Potassium-Exchanging ATPase; D035361:Transcription Factor TFIIIB; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C427472:BDP1 protein, human