The unpredicted high affinities of a large number of naturally occurring tachykinins for chimeric NK1/NK3 receptors suggest a role for an inhibitory domain in determining receptor specificity
Three chimeric receptors were constructed by exchanging exon sequences between human NK1 and NK3 receptor genes. The resulting chimeric receptors not only retained high affinities for their natural ligands substance P and neurokinin B but also exhibited surprisingly high affinities for other naturally occurring tachykinins including neurokinin A, neuropeptide K, neuropeptide gamma, eledoisin, kassinin, physalaemin, and phyllomedusin. In contrast, these chimeric receptors displayed a wide range of variability in their affinities for non-naturally occurring ligands including selective agonists and antagonists of NK1, NK2, and NK3 receptors. Since the only common feature among these naturally occurring neurokinin peptides is the conserved C-terminal sequences, our data suggest that these conserved sequences must play the major role in conferring high affinity binding to the chimeric receptors. To explain the apparently "improved" affinities of these naturally occurring ligands for the chimeric receptors as compared with their affinities for the parent NK1 and NK3 receptors, we are proposing that certain inhibitory domains that are present in the NK1 and/or NK3 receptors are compromised in these chimeric receptors. Upon disruption of these inhibitory domains during the formation of chimeras, the naturally occurring ligands can interact more favorably with chimeric receptors through their conserved C-terminal sequences. Based on this hypothesis, the binding affinities of natural tachykinin ligands may be largely determined by their conserved C-terminal sequences, whereas receptor selectivities of these ligands are influenced more by the presence or absence of inhibitory domains rather than specific binding domains on their target receptors.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
1996 |
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| Erschienen: |
1996 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:271 |
|---|---|
| Enthalten in: |
The Journal of biological chemistry - 271(1996), 34 vom: 23. Aug., Seite 20250-7 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tian, Y [VerfasserIn] |
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| Anmerkungen: |
Date Completed 11.10.1996 Date Revised 10.02.2021 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM086750305 |
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| 100 | 1 | |a Tian, Y |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The unpredicted high affinities of a large number of naturally occurring tachykinins for chimeric NK1/NK3 receptors suggest a role for an inhibitory domain in determining receptor specificity |
| 264 | 1 | |c 1996 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 11.10.1996 | ||
| 500 | |a Date Revised 10.02.2021 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Three chimeric receptors were constructed by exchanging exon sequences between human NK1 and NK3 receptor genes. The resulting chimeric receptors not only retained high affinities for their natural ligands substance P and neurokinin B but also exhibited surprisingly high affinities for other naturally occurring tachykinins including neurokinin A, neuropeptide K, neuropeptide gamma, eledoisin, kassinin, physalaemin, and phyllomedusin. In contrast, these chimeric receptors displayed a wide range of variability in their affinities for non-naturally occurring ligands including selective agonists and antagonists of NK1, NK2, and NK3 receptors. Since the only common feature among these naturally occurring neurokinin peptides is the conserved C-terminal sequences, our data suggest that these conserved sequences must play the major role in conferring high affinity binding to the chimeric receptors. To explain the apparently "improved" affinities of these naturally occurring ligands for the chimeric receptors as compared with their affinities for the parent NK1 and NK3 receptors, we are proposing that certain inhibitory domains that are present in the NK1 and/or NK3 receptors are compromised in these chimeric receptors. Upon disruption of these inhibitory domains during the formation of chimeras, the naturally occurring ligands can interact more favorably with chimeric receptors through their conserved C-terminal sequences. Based on this hypothesis, the binding affinities of natural tachykinin ligands may be largely determined by their conserved C-terminal sequences, whereas receptor selectivities of these ligands are influenced more by the presence or absence of inhibitory domains rather than specific binding domains on their target receptors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a Phosphatidylinositols |2 NLM | |
| 650 | 7 | |a Receptors, Neurokinin-1 |2 NLM | |
| 650 | 7 | |a Receptors, Neurokinin-3 |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a Tachykinins |2 NLM | |
| 650 | 7 | |a Substance P |2 NLM | |
| 650 | 7 | |a 33507-63-0 |2 NLM | |
| 650 | 7 | |a Neurokinin A |2 NLM | |
| 650 | 7 | |a 86933-74-6 |2 NLM | |
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| 700 | 1 | |a Wu, L H |e verfasserin |4 aut | |
| 700 | 1 | |a Oxender, D L |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, F Z |e verfasserin |4 aut | |
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