Lysophosphatidic acid regulates trafficking of beta2-adrenergic receptors: the Galpha13/p115RhoGEF/JNK pathway stimulates receptor internalization.
Lysophosphatidic acid is an important lipid ligand regulating many aspects of cell function, including proliferation and migration. Operating via heterotrimeric G proteins to downstream effectors, lysophosphatidic acid was shown to regulate the function and trafficking of the G protein-coupled beta(2)-adrenergic receptor. C3 exotoxin, expression of dominant negative RhoA, and inhibition of c-Jun N-terminal kinase blocked the ability of lysophosphatidic acid to sequester the beta(2)-adrenergic receptor, whereas expression of constitutively active Galpha(13), p115RhoGEF, or RhoA mimicked lysophosphatidic acid (LPA) action, stimulating the internalization of the Galpha(s)-coupled beta(2)-adrenergic receptor. This study revealed a novel cross-talk exerted from the LPA/Galpha(13)/p115RhoGEF/RhoA pathway to the beta(2)-adrenergic receptor/Galpha(s)/adenylyl cyclase pathway, attenuating the ability of beta-adrenergic agonists to act following stimulation of cells by LPA as may occur during beta-adrenergic therapy of an inflammatory response.
Shumay
Elena
E
Department of Pharmacology, Diabetes and Metabolic Diseases Research Program, School of Medicine, State University of New York, Stony Brook, New York 11794-8661, USA.
Tao
Jiangchuan
J
Wang
Hsien-Yu
HY
Malbon
Craig C
CC
D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D005799:Genes, Dominant; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D008246:Lysophospholipids / Q000378:metabolism / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D018613:Microscopy, Confocal; D008954:Models, Biological; D021381:Protein Transport; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D008246:Lysophospholipids; D018343:Receptors, Adrenergic, beta-2; D064067:Rho Guanine Nucleotide Exchange Factors; D048670:MAP Kinase Kinase 4; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein; C032881:lysophosphatidic acid