Antagonism of catecholamine receptor signaling by expression of cytoplasmic domains of the receptors.
The actions of many hormones and neurotransmitters are mediated by the members of a superfamily of receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins). These receptors are characterized by a highly conserved topographical arrangement in which seven transmembrane domains are connected by intracellular and extracellular loops. The interaction between these receptors and G proteins is mediated in large part by the third intracellular loop of the receptor. Coexpression of the third intracellular loop of the alpha 1B-adrenergic receptor with its parent receptor inhibited receptor-mediated activation of phospholipase C. The inhibition extended to the closely related alpha 1C-adrenergic receptor subtype, but not the phospholipase C-coupled M1 muscarinic acetylcholine receptor nor the adenylate cyclase-coupled D1A dopamine receptor. These results suggest that the receptor-G protein interface may represent a target for receptor antagonist drugs.
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
L M
LM
Luttrell
J
J
Ostrowski
S
S
Cotecchia
H
H
Kendall
R J
RJ
Lefkowitz
D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005914:Globins / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D018727:Muscarinic Antagonists; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D017433:Protein Structure, Secondary; D011942:Receptors, Adrenergic, alpha / Q000235:genetics / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D007295:Inositol Phosphates; D018727:Muscarinic Antagonists; D009838:Oligodeoxyribonucleotides; D011942:Receptors, Adrenergic, alpha; D017447:Receptors, Dopamine D1; D011976:Receptors, Muscarinic; D011993:Recombinant Fusion Proteins; D005914:Globins; D000242:Cyclic AMP; D005982:Glutathione Transferase; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins