Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model
Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as a...
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todo:paper_0026895X_v64_n2_p512_Monczor2023-10-03T14:37:13Z Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model Monczor, F. Fernández, N. Legnazzi, B.L. Riveiro, M.E. Baldi, A. Shayo, C. Davio, C. beta 2 adrenergic receptor G protein coupled receptor guanosine 5' o (3 thiotriphosphate) histamine H2 receptor histamine H2 receptor agonist histamine H2 receptor antagonist tiotidine animal cell article controlled study dose response drug activity drug receptor binding drug use human human cell nonhuman priority journal signal transduction Animals Cimetidine COS Cells Dose-Response Relationship, Drug Histamine Agonists Histamine H2 Antagonists Humans Models, Biological Receptors, Histamine H2 Transfection Tritium Tumor Cells, Cultured U937 Cells Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5′-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Gαs-protein (β2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Gαs-coupled form of the H2 receptor and turns Gαs-protein less available to interact with β2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model. Fil:Fernández, N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Shayo, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_0026895X_v64_n2_p512_Monczor |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
beta 2 adrenergic receptor G protein coupled receptor guanosine 5' o (3 thiotriphosphate) histamine H2 receptor histamine H2 receptor agonist histamine H2 receptor antagonist tiotidine animal cell article controlled study dose response drug activity drug receptor binding drug use human human cell nonhuman priority journal signal transduction Animals Cimetidine COS Cells Dose-Response Relationship, Drug Histamine Agonists Histamine H2 Antagonists Humans Models, Biological Receptors, Histamine H2 Transfection Tritium Tumor Cells, Cultured U937 Cells |
| spellingShingle |
beta 2 adrenergic receptor G protein coupled receptor guanosine 5' o (3 thiotriphosphate) histamine H2 receptor histamine H2 receptor agonist histamine H2 receptor antagonist tiotidine animal cell article controlled study dose response drug activity drug receptor binding drug use human human cell nonhuman priority journal signal transduction Animals Cimetidine COS Cells Dose-Response Relationship, Drug Histamine Agonists Histamine H2 Antagonists Humans Models, Biological Receptors, Histamine H2 Transfection Tritium Tumor Cells, Cultured U937 Cells Monczor, F. Fernández, N. Legnazzi, B.L. Riveiro, M.E. Baldi, A. Shayo, C. Davio, C. Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| topic_facet |
beta 2 adrenergic receptor G protein coupled receptor guanosine 5' o (3 thiotriphosphate) histamine H2 receptor histamine H2 receptor agonist histamine H2 receptor antagonist tiotidine animal cell article controlled study dose response drug activity drug receptor binding drug use human human cell nonhuman priority journal signal transduction Animals Cimetidine COS Cells Dose-Response Relationship, Drug Histamine Agonists Histamine H2 Antagonists Humans Models, Biological Receptors, Histamine H2 Transfection Tritium Tumor Cells, Cultured U937 Cells |
| description |
Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5′-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Gαs-protein (β2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Gαs-coupled form of the H2 receptor and turns Gαs-protein less available to interact with β2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model. |
| format |
JOUR |
| author |
Monczor, F. Fernández, N. Legnazzi, B.L. Riveiro, M.E. Baldi, A. Shayo, C. Davio, C. |
| author_facet |
Monczor, F. Fernández, N. Legnazzi, B.L. Riveiro, M.E. Baldi, A. Shayo, C. Davio, C. |
| author_sort |
Monczor, F. |
| title |
Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| title_short |
Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| title_full |
Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| title_fullStr |
Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| title_full_unstemmed |
Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model |
| title_sort |
tiotidine, a histamine h2 receptor inverse agonist that binds with high affinity to an inactive g-protein-coupled form of the receptor. experimental support for the cubic ternary complex model |
| url |
http://hdl.handle.net/20.500.12110/paper_0026895X_v64_n2_p512_Monczor |
| work_keys_str_mv |
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