β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor
Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7–34), a PTH derivative that is said to preferentially activate β-a...
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| Veröffentlicht in: | Cellular signalling 2013-02, Vol.25 (2), p.527-538 |
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| creator | van der Lee, Miranda M.C. Verkaar, Folkert Wat, Jesse W.Y. van Offenbeek, Jody Timmerman, Martijn Voorneveld, Lonneke van Lith, Lambertus H.C.J. Zaman, Guido J.R. |
| description | Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7–34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7–34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gαs- and Gαq-signaling. We found that PTH(7–34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7–34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7–34) to in vitro pharmacology should be done with caution.
► We made a platform to measure PTH1R signaling to cAMP, Ca2+ and β-arrestin. ► Our assays provide opportunities for identifying biased ligands for PTH1R. ► A presumed β-arrestin-biased PTH derivative (PTH(7–34)) did not activate β-arrestin. ► PTH(7–34)-mediated β-arrestin signaling may be cell type-specific. |
| doi_str_mv | 10.1016/j.cellsig.2012.11.012 |
| format | Article |
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► We made a platform to measure PTH1R signaling to cAMP, Ca2+ and β-arrestin. ► Our assays provide opportunities for identifying biased ligands for PTH1R. ► A presumed β-arrestin-biased PTH derivative (PTH(7–34)) did not activate β-arrestin. ► PTH(7–34)-mediated β-arrestin signaling may be cell type-specific.</description><identifier>ISSN: 0898-6568</identifier><identifier>EISSN: 1873-3913</identifier><identifier>DOI: 10.1016/j.cellsig.2012.11.012</identifier><identifier>PMID: 23159578</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Activation ; Animals ; Arrestins - metabolism ; beta-Arrestins ; Biased agonist ; Bones ; Calcium - metabolism ; Cell Line ; Cellular ; CHO Cells ; Cricetinae ; Cricetulus ; Cyclic AMP - metabolism ; Derivatives ; Hormones ; Humans ; Low molecular weight ; Mice ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Parathyroid Hormone - analogs & derivatives ; Parathyroid Hormone - pharmacology ; Parathyroid hormone receptor ; Phosphorylation ; PTH(7–34) ; PTHβarr ; Receptor, Parathyroid Hormone, Type 1 - agonists ; Receptor, Parathyroid Hormone, Type 1 - metabolism ; Receptors ; Recruitment ; Signal Transduction - drug effects ; Signalling ; β-Arrestin</subject><ispartof>Cellular signalling, 2013-02, Vol.25 (2), p.527-538</ispartof><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-8ba82a630b7830db093d35e001b99b2a4797d45381802423f9f470e5e28700313</citedby><cites>FETCH-LOGICAL-c398t-8ba82a630b7830db093d35e001b99b2a4797d45381802423f9f470e5e28700313</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cellsig.2012.11.012$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23159578$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van der Lee, Miranda M.C.</creatorcontrib><creatorcontrib>Verkaar, Folkert</creatorcontrib><creatorcontrib>Wat, Jesse W.Y.</creatorcontrib><creatorcontrib>van Offenbeek, Jody</creatorcontrib><creatorcontrib>Timmerman, Martijn</creatorcontrib><creatorcontrib>Voorneveld, Lonneke</creatorcontrib><creatorcontrib>van Lith, Lambertus H.C.J.</creatorcontrib><creatorcontrib>Zaman, Guido J.R.</creatorcontrib><title>β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor</title><title>Cellular signalling</title><addtitle>Cell Signal</addtitle><description>Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7–34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7–34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gαs- and Gαq-signaling. We found that PTH(7–34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7–34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7–34) to in vitro pharmacology should be done with caution.
► We made a platform to measure PTH1R signaling to cAMP, Ca2+ and β-arrestin. ► Our assays provide opportunities for identifying biased ligands for PTH1R. ► A presumed β-arrestin-biased PTH derivative (PTH(7–34)) did not activate β-arrestin. ► PTH(7–34)-mediated β-arrestin signaling may be cell type-specific.</description><subject>Activation</subject><subject>Animals</subject><subject>Arrestins - metabolism</subject><subject>beta-Arrestins</subject><subject>Biased agonist</subject><subject>Bones</subject><subject>Calcium - metabolism</subject><subject>Cell Line</subject><subject>Cellular</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclic AMP - metabolism</subject><subject>Derivatives</subject><subject>Hormones</subject><subject>Humans</subject><subject>Low molecular weight</subject><subject>Mice</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Parathyroid Hormone - analogs & derivatives</subject><subject>Parathyroid Hormone - pharmacology</subject><subject>Parathyroid hormone receptor</subject><subject>Phosphorylation</subject><subject>PTH(7–34)</subject><subject>PTHβarr</subject><subject>Receptor, Parathyroid Hormone, Type 1 - agonists</subject><subject>Receptor, Parathyroid Hormone, Type 1 - metabolism</subject><subject>Receptors</subject><subject>Recruitment</subject><subject>Signal Transduction - drug effects</subject><subject>Signalling</subject><subject>β-Arrestin</subject><issn>0898-6568</issn><issn>1873-3913</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMFq3DAQhkVpSLZJHqFBx17saiTLlk5lCW23EEgOSa5Ctse7WryWK3kD-1p9kD5TZXbT66LDz8A3M5qPkM_AcmBQft3mDfZ9dOucM-A5QJ7iA1mAqkQmNIiPZMGUVlkpS3VFPsW4ZQwkK_klueICpJaVWpDXv3-yZQgYJzdktbMRW5qGDrZ3w5r6jj49r6hNpV_HuZw2SKfDiBToaIOdNofgXUs3Puz8gDRgg-Pkww256Gwf8faU1-Tlx_fn-1X28Pjz1_3yIWuEVlOmaqu4LQWrKyVYWzMtWiExfbTWuua2qHTVFlIoUIwXXHS6KyqGErmqGBMgrsmX49wx-N_7dIXZuTiLsQP6fTSQDi2LItHnUV6JQs4vofKINsHHGLAzY3A7Gw4GmJntm6052TezfQNgUqS-u9OKfb3D9n_Xu-4EfDsCmJy8OQwmNg6HBluXzE2m9e7Min8kwZb7</recordid><startdate>201302</startdate><enddate>201302</enddate><creator>van der Lee, Miranda M.C.</creator><creator>Verkaar, Folkert</creator><creator>Wat, Jesse W.Y.</creator><creator>van Offenbeek, Jody</creator><creator>Timmerman, Martijn</creator><creator>Voorneveld, Lonneke</creator><creator>van Lith, Lambertus H.C.J.</creator><creator>Zaman, Guido J.R.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7U5</scope><scope>8FD</scope><scope>L7M</scope></search><sort><creationdate>201302</creationdate><title>β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor</title><author>van der Lee, Miranda M.C. ; Verkaar, Folkert ; Wat, Jesse W.Y. ; van Offenbeek, Jody ; Timmerman, Martijn ; Voorneveld, Lonneke ; van Lith, Lambertus H.C.J. ; Zaman, Guido J.R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c398t-8ba82a630b7830db093d35e001b99b2a4797d45381802423f9f470e5e28700313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Activation</topic><topic>Animals</topic><topic>Arrestins - metabolism</topic><topic>beta-Arrestins</topic><topic>Biased agonist</topic><topic>Bones</topic><topic>Calcium - metabolism</topic><topic>Cell Line</topic><topic>Cellular</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclic AMP - metabolism</topic><topic>Derivatives</topic><topic>Hormones</topic><topic>Humans</topic><topic>Low molecular weight</topic><topic>Mice</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Parathyroid Hormone - analogs & derivatives</topic><topic>Parathyroid Hormone - pharmacology</topic><topic>Parathyroid hormone receptor</topic><topic>Phosphorylation</topic><topic>PTH(7–34)</topic><topic>PTHβarr</topic><topic>Receptor, Parathyroid Hormone, Type 1 - agonists</topic><topic>Receptor, Parathyroid Hormone, Type 1 - metabolism</topic><topic>Receptors</topic><topic>Recruitment</topic><topic>Signal Transduction - drug effects</topic><topic>Signalling</topic><topic>β-Arrestin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>van der Lee, Miranda M.C.</creatorcontrib><creatorcontrib>Verkaar, Folkert</creatorcontrib><creatorcontrib>Wat, Jesse W.Y.</creatorcontrib><creatorcontrib>van Offenbeek, Jody</creatorcontrib><creatorcontrib>Timmerman, Martijn</creatorcontrib><creatorcontrib>Voorneveld, Lonneke</creatorcontrib><creatorcontrib>van Lith, Lambertus H.C.J.</creatorcontrib><creatorcontrib>Zaman, Guido J.R.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Technology Research Database</collection><collection>Advanced Technologies Database with Aerospace</collection><jtitle>Cellular signalling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van der Lee, Miranda M.C.</au><au>Verkaar, Folkert</au><au>Wat, Jesse W.Y.</au><au>van Offenbeek, Jody</au><au>Timmerman, Martijn</au><au>Voorneveld, Lonneke</au><au>van Lith, Lambertus H.C.J.</au><au>Zaman, Guido J.R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor</atitle><jtitle>Cellular signalling</jtitle><addtitle>Cell Signal</addtitle><date>2013-02</date><risdate>2013</risdate><volume>25</volume><issue>2</issue><spage>527</spage><epage>538</epage><pages>527-538</pages><issn>0898-6568</issn><eissn>1873-3913</eissn><abstract>Parathyroid hormone (PTH) is an anabolic agent that mediates bone formation through activation of the Gαs-, Gαq- and β-arrestin-coupled parathyroid hormone receptor type 1 (PTH1R). Pharmacological evidence based on the effect of PTH(7–34), a PTH derivative that is said to preferentially activate β-arrestin signaling through PTH1R, suggests that PTH1R-activated β-arrestin signaling mediates anabolic effects on bone. Here, we performed a thorough evaluation of PTH(7–34) signaling behaviour using quantitative assays for β-arrestin recruitment, Gαs- and Gαq-signaling. We found that PTH(7–34) inhibited PTH-induced cAMP accumulation, but was unable to induce β-arrestin recruitment, PTH1R internalization and ERK1/2 phosphorylation in HEK293, CHO and U2OS cells. Thus, the β-arrestin bias of PTH(7–34) is not apparent in every cell type examined, suggesting that correlating in vivo effects of PTH(7–34) to in vitro pharmacology should be done with caution.
► We made a platform to measure PTH1R signaling to cAMP, Ca2+ and β-arrestin. ► Our assays provide opportunities for identifying biased ligands for PTH1R. ► A presumed β-arrestin-biased PTH derivative (PTH(7–34)) did not activate β-arrestin. ► PTH(7–34)-mediated β-arrestin signaling may be cell type-specific.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>23159578</pmid><doi>10.1016/j.cellsig.2012.11.012</doi><tpages>12</tpages></addata></record> |
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| subjects | Activation Animals Arrestins - metabolism beta-Arrestins Biased agonist Bones Calcium - metabolism Cell Line Cellular CHO Cells Cricetinae Cricetulus Cyclic AMP - metabolism Derivatives Hormones Humans Low molecular weight Mice Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Parathyroid Hormone - analogs & derivatives Parathyroid Hormone - pharmacology Parathyroid hormone receptor Phosphorylation PTH(7–34) PTHβarr Receptor, Parathyroid Hormone, Type 1 - agonists Receptor, Parathyroid Hormone, Type 1 - metabolism Receptors Recruitment Signal Transduction - drug effects Signalling β-Arrestin |
| title | β-Arrestin-biased signaling of PTH analogs of the type 1 parathyroid hormone receptor |
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