Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor
β-blockers are widely used to improve symptoms and prolong life in heart disease primarily by inhibiting the actions of endogenous catecholamines at the β1-adrenoceptor. There are two common naturally occurring polymorphisms within the human β1-adrenoceptor sequence: Ser or Gly at position 49 in the...
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| Format: | Article |
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Public Library of Science
2013
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| Online Access: | https://eprints.nottingham.ac.uk/2360/ |
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| author | Baker, Jillian G. Hill, Stephen J. Proudman, Richard G.W. |
| author_facet | Baker, Jillian G. Hill, Stephen J. Proudman, Richard G.W. |
| author_sort | Baker, Jillian G. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | β-blockers are widely used to improve symptoms and prolong life in heart disease primarily by inhibiting the actions of endogenous catecholamines at the β1-adrenoceptor. There are two common naturally occurring polymorphisms within the human β1-adrenoceptor sequence: Ser or Gly at position 49 in the N-terminus and Gly or Arg at position 389 in the C-terminus and some clinical studies have suggested that expression of certain variants may be associated with disease and affect response to treatment with β-blockers. The β1-adrenoceptor also exists in two agonist conformations - a high affinity catecholamine conformation and a low affinity secondary agonist conformation. Receptor-effector coupling and intracellular signalling from the different conformations may be affected by the polymorphic variants.
Here, we examine in detail the molecular pharmacology of the β1-adrenoceptor polymorphic variants with respect to ligand affinity, efficacy, activation of the different agonist conformations and signal transduction and determine whether the polymorphic variants do indeed affect this secondary conformation. Stable cell lines expressing the wildtype and polymorphic variants were constructed and receptor pharmacology examined using whole cell binding and intracellular secondary messenger techniques.
There was no difference in affinity for agonists and antagonists at the human wildtype β1-adrenoceptor (Ser49/Gly389) and the polymorphic variants Gly49/Gly389 and Ser49/Arg389. Furthermore, the polymorphic variant receptors both have two active agonist conformations with pharmacological properties similar to the wildtype receptor. Although the polymorphism at position 389 is thought to occur in an intracellular domain important for Gs-coupling, the two agonist conformations of the polymorphic variants stimulate intracellular signalling pathways, including Gs-cAMP intracellular signalling, in a manner very similar to that of the wildtype receptor. |
| first_indexed | 2025-11-14T18:17:48Z |
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| id | nottingham-2360 |
| institution | University of Nottingham Malaysia Campus |
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| last_indexed | 2025-11-14T18:17:48Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
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| spelling | nottingham-23602020-05-04T16:39:58Z https://eprints.nottingham.ac.uk/2360/ Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor Baker, Jillian G. Hill, Stephen J. Proudman, Richard G.W. β-blockers are widely used to improve symptoms and prolong life in heart disease primarily by inhibiting the actions of endogenous catecholamines at the β1-adrenoceptor. There are two common naturally occurring polymorphisms within the human β1-adrenoceptor sequence: Ser or Gly at position 49 in the N-terminus and Gly or Arg at position 389 in the C-terminus and some clinical studies have suggested that expression of certain variants may be associated with disease and affect response to treatment with β-blockers. The β1-adrenoceptor also exists in two agonist conformations - a high affinity catecholamine conformation and a low affinity secondary agonist conformation. Receptor-effector coupling and intracellular signalling from the different conformations may be affected by the polymorphic variants. Here, we examine in detail the molecular pharmacology of the β1-adrenoceptor polymorphic variants with respect to ligand affinity, efficacy, activation of the different agonist conformations and signal transduction and determine whether the polymorphic variants do indeed affect this secondary conformation. Stable cell lines expressing the wildtype and polymorphic variants were constructed and receptor pharmacology examined using whole cell binding and intracellular secondary messenger techniques. There was no difference in affinity for agonists and antagonists at the human wildtype β1-adrenoceptor (Ser49/Gly389) and the polymorphic variants Gly49/Gly389 and Ser49/Arg389. Furthermore, the polymorphic variant receptors both have two active agonist conformations with pharmacological properties similar to the wildtype receptor. Although the polymorphism at position 389 is thought to occur in an intracellular domain important for Gs-coupling, the two agonist conformations of the polymorphic variants stimulate intracellular signalling pathways, including Gs-cAMP intracellular signalling, in a manner very similar to that of the wildtype receptor. Public Library of Science 2013-11-08 Article PeerReviewed Baker, Jillian G., Hill, Stephen J. and Proudman, Richard G.W. (2013) Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor. PLoS ONE, 8 (11). ISSN 1932-6203 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0077582 doi:10.1371/journal.pone.0077582 doi:10.1371/journal.pone.0077582 |
| spellingShingle | Baker, Jillian G. Hill, Stephen J. Proudman, Richard G.W. Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title | Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title_full | Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title_fullStr | Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title_full_unstemmed | Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title_short | Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| title_sort | impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor |
| url | https://eprints.nottingham.ac.uk/2360/ https://eprints.nottingham.ac.uk/2360/ https://eprints.nottingham.ac.uk/2360/ |