Distinct function of the cytoplasmic tail in human D1-like receptor ligand binding and coupling.
To delineate the role of the cytoplasmic tail in the distinct binding and coupling properties of human dopamine D1-like receptors, chimeric receptors were generated in which the entire tail region of wild-type human D1A (or D1) and D1B (or D5) receptors was exchanged. The hD1A-D1BT, but not hD1B-D1AT, receptor expression was dramatically reduced compared with wild-type receptor expression. Swapping the cytoplasmic tail resulted in a full switch of dopamine binding affinity and constitutive activity, while dopamine potency decreased and agonist-mediated maximal activation of adenylyl cyclase increased for both chimeras. Hence, the cytoplasmic tail plays a crucial role in D1-like receptor expression, agonist binding affinity and constitutive activation but regulates in a distinct fashion the formation of D1A and D1B receptor active states upon dopamine binding.
Jackson
A
A
Neurosciences, Loeb Health Research Institute, Ottawa Hospital (Civic Campus) and Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada.
Iwasiow
R M
RM
Tiberi
M
M
D000262:Adenylyl Cyclases / Q000378:metabolism; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050641:Receptors, Dopamine D5; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014162:Transfection
D014150:Antipsychotic Agents; C493605:DRD5 protein, human; D018492:Dopamine Antagonists; D008024:Ligands; D017447:Receptors, Dopamine D1; D011993:Recombinant Fusion Proteins; C098593:dopamine D1A receptor; D050641:Receptors, Dopamine D5; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D004298:Dopamine