ArticleThe Journal of biological chemistry2004
Agonist versus antagonist action of ATP at the P2Y4 receptor is determined by the second extracellular loop.
Article in The Journal of biological chemistry, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 47 citations in OpenAlex.
- Physiology and pathophysiology of human airway mucus.Physiological reviews · 2022Review
- Loss-of-function N178T variant of the human P2YFrontiers in pharmacology · 2022Article
- Medicinal chemistry of P2 and adenosine receptors: Common scaffolds adapted for multiple targets.Biochemical pharmacology · 2021Review
- P2 Receptors in Cardiac Myocyte Pathophysiology and Mechanotransduction.International journal of molecular sciences · 2020Review
- P2YPurinergic signalling · 2018Article
- Medicinal chemistry of adenosine, P2Y and P2X receptors.Neuropharmacology · 2016Review
- Nucleotides Acting at P2Y Receptors: Connecting Structure and Function.Molecular pharmacology · 2015Review
- P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential.CNS & neurological disorders drug targets · 2012Review
- Role of the transmembrane domain 4/extracellular loop 2 junction of the human gonadotropin-releasing hormone receptor in ligand binding and receptor conformational selection.The Journal of biological chemistry · 2011Article
- Agonist-selective, receptor-specific interaction of human P2Y receptors with beta-arrestin-1 and -2.The Journal of biological chemistry · 2008Article
- UDP is a competitive antagonist at the human P2Y14 receptor.The Journal of pharmacology and experimental therapeutics · 2008Article
- The P2Y₄ receptor forms homo-oligomeric complexes in several CNS and PNS neuronal cells.Purinergic signalling · 2006Article
- Integration of P2Y receptor-activated signal transduction pathways in G protein-dependent signalling networks.Purinergic signalling · 2006Article
- International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy.Pharmacological reviews · 2006Review
- Shift in purine/pyrimidine base recognition upon exchanging extracellular domains in P2Y 1/6 chimeric receptors.Biochemical pharmacology · 2004Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
UTP is a potent full agonist at both the human P2Y(4) (hP2Y(4)) and rat P2Y(4) (rP2Y(4)) receptor. In contrast, ATP is a potent full agonist at the rP2Y(4) receptor but is a similarly potent competitive antagonist at the hP2Y(4) receptor. To delineate the structural determinants of agonism versus antagonism in these species homologues, we expressed a series of human/rat P2Y(4) receptor chimeras in 1321N1 human astrocytoma cells and assessed the capacity of ATP and UTP to mobilize intracellular Ca(2+). Replacement of the NH(2) terminus of the hP2Y(4) receptor with the corresponding region of the rP2Y(4) receptor resulted in a receptor that was activated weakly by ATP, whereas replacement of the second extracellular loop (EL2) of the hP2Y(4) receptor with that of the rP2Y(4) receptor yielded a chimeric receptor that was activated fully by UTP and near fully by ATP, albeit with lower potencies than those observed at the rP2Y(4) receptor. These potencies were increased, and ATP was converted to a full agonist by replacing both the NH(2) terminus and EL2 in the hP2Y(4) receptor with the corresponding regions from the rP2Y(4) receptor. Mutational analysis of the five divergent amino acids in EL2 between the two receptors revealed that three amino acids, Asn-177, Ile-183, and Leu-190, contribute to the capacity of EL2 to impart ATP agonism. Taken together, these results suggest that the second extracellular loop and the NH(2) terminus form a functional motif that plays a key role in determining whether ATP functions as an agonist or antagonist at mammalian P2Y(4) receptors.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.