title: Agonist-induced changes in RalA activities allows the prediction of the endocytosis of G protein-coupled receptors.
abstract: GTP binding proteins are classified into two families: heterotrimeric large G proteins which are composed of three subunits, and one subunit of small G proteins. Roles of small G proteins in the intracellular trafficking of G protein-coupled receptors (GPCRs) were studied. Among various small G proteins tested, GTP-bound form (G23V) of RalA inhibited the internalization of dopamine D2 receptor independently of the previously reported downstream effectors of RalA, such as Ral-binding protein 1 and PLD. With high affinity for GRK2, active RalA inhibited the GPCR endocytosis by sequestering the GRK2 from receptors. When it was tested for several GPCRs including an endogenous GPCR, lysophosphatidic acid receptor 1, agonist-induced conversion of GTP-bound to GDP-bound RalA, which presumably releases the sequestered GRK2, was observed selectively with the GPCRs which have tendency to undergo endocytosis. Conversion of RalA from active to inactive state occurred by translocation of RGL, a guanine nucleotide exchange factor, from the plasma membrane to cytosol as a complex with Gβγ. These results suggest that agonist-induced Gβγ-mediated conversion of RalA from the GTP-bound form to the GDP-bound form could be a mechanism to facilitate agonist-induced internalization of GPCRs.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Mei
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Shuohan
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Chengchun
authors.initials: C
authors.lastname: Min
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Seung Hoon
authors.initials: SH
authors.lastname: Cheon
authors.affiliation: College of Pharmacy, Mokpo National University, Muan-gun, Jeollanamdo 534-729, Republic of Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Oak
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea.
authors.forename: Young Ran
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Republic of Korea. Electronic address: kmkim@jnu.ac.kr.
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
mesh_terms: D004705:Endocytosis / Q000502:physiology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D021381:Protein Transport / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017448:Receptors, Dopamine D2; D049368:Receptors, Lysophosphatidic Acid; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
keywords: Angiotensin; Epsin; LPA; β-Adrenoceptor; β-Arrestin