Homologous and Heterologous Regulation of Somatostatin Receptor 2
We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in...
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Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2002-11, Vol.16 (11), p.2502-2514 |
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description | We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in the homologous or heterologous regulation of endogenous sst2 receptors in AR42J pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK) or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all stimulated this internalization further. Additionally, sst2 receptor-mediated inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin, as well as peptidic (SMS201–995) and nonpeptidic (L-779,976) sst2 receptor agonists increased the EC50 for somatostatin inhibition 20-fold. In contrast, pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC50 for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of somatostatin, demonstrating that these reactions were catalyzed by different kinases. Consistent with a functional role for PKC-mediated receptor phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK stimulation of sst2A receptor endocytosis. These results demonstrate that homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC-independent and -dependent mechanisms, respectively, and produce distinct effects on receptor signaling and internalization. In addition, the heterologous hormones also modulate sst2 receptor internalization by a novel mechanism that is independent of receptor phosphorylation. |
doi_str_mv | 10.1210/me.2002-0207 |
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William ; Schonbrunn, Agnes</creator><creatorcontrib>Elberg, Gerard ; Hipkin, R. William ; Schonbrunn, Agnes</creatorcontrib><description>We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in the homologous or heterologous regulation of endogenous sst2 receptors in AR42J pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK) or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all stimulated this internalization further. Additionally, sst2 receptor-mediated inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin, as well as peptidic (SMS201–995) and nonpeptidic (L-779,976) sst2 receptor agonists increased the EC50 for somatostatin inhibition 20-fold. In contrast, pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC50 for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of somatostatin, demonstrating that these reactions were catalyzed by different kinases. Consistent with a functional role for PKC-mediated receptor phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK stimulation of sst2A receptor endocytosis. These results demonstrate that homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC-independent and -dependent mechanisms, respectively, and produce distinct effects on receptor signaling and internalization. In addition, the heterologous hormones also modulate sst2 receptor internalization by a novel mechanism that is independent of receptor phosphorylation.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2002-0207</identifier><identifier>PMID: 12403839</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Adenylyl Cyclase Inhibitors ; Amides - pharmacology ; Animals ; Cell Line ; Indoles - pharmacology ; Octreotide - pharmacology ; Pancreas ; Phosphorylation ; Protein Kinase C - metabolism ; Rats ; Receptors, Somatostatin - drug effects ; Receptors, Somatostatin - genetics ; Receptors, Somatostatin - metabolism ; Somatostatin - pharmacology ; Tetradecanoylphorbol Acetate - pharmacology</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2002-11, Vol.16 (11), p.2502-2514</ispartof><rights>Copyright © 2002 by The Endocrine Society 2002</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c401t-5651e5371c744bcf74dc3108f868a554f7ecb6b7a136b112676c4a31f596921b3</citedby><cites>FETCH-LOGICAL-c401t-5651e5371c744bcf74dc3108f868a554f7ecb6b7a136b112676c4a31f596921b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12403839$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Elberg, Gerard</creatorcontrib><creatorcontrib>Hipkin, R. William</creatorcontrib><creatorcontrib>Schonbrunn, Agnes</creatorcontrib><title>Homologous and Heterologous Regulation of Somatostatin Receptor 2</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in the homologous or heterologous regulation of endogenous sst2 receptors in AR42J pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK) or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all stimulated this internalization further. Additionally, sst2 receptor-mediated inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin, as well as peptidic (SMS201–995) and nonpeptidic (L-779,976) sst2 receptor agonists increased the EC50 for somatostatin inhibition 20-fold. In contrast, pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC50 for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of somatostatin, demonstrating that these reactions were catalyzed by different kinases. Consistent with a functional role for PKC-mediated receptor phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK stimulation of sst2A receptor endocytosis. These results demonstrate that homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC-independent and -dependent mechanisms, respectively, and produce distinct effects on receptor signaling and internalization. In addition, the heterologous hormones also modulate sst2 receptor internalization by a novel mechanism that is independent of receptor phosphorylation.</description><subject>Adenylyl Cyclase Inhibitors</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Indoles - pharmacology</subject><subject>Octreotide - pharmacology</subject><subject>Pancreas</subject><subject>Phosphorylation</subject><subject>Protein Kinase C - metabolism</subject><subject>Rats</subject><subject>Receptors, Somatostatin - drug effects</subject><subject>Receptors, Somatostatin - genetics</subject><subject>Receptors, Somatostatin - metabolism</subject><subject>Somatostatin - pharmacology</subject><subject>Tetradecanoylphorbol Acetate - pharmacology</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kM1Lw0AUxBdRbK3ePEtuXkzdtx_ZzbGUaoWC4Md52WxeSkuTDbvJwf_elFS86OnBvB_DzBByC3QODOhjjXNGKUspo-qMTCEXIs1zUOdkSrXWqdY0n5CrGPeUgpAaLskEmKBc83xKFmtf-4Pf-j4mtimTNXYYfoQ33PYH2-18k_gqefe17XzsBqEZXg7bzoeEXZOLyh4i3pzujHw-rT6W63Tz-vyyXGxSJyh0qcwkoOQKnBKicJUSpeNAdaUzbaUUlUJXZIWywLMCgGUqc8JyqGSe5QwKPiMPo68LPsaAlWnDrrbhywA1xyVMjea4hDkuMeB3I972RY3lL3yqPgD3I-D79j-r9GTFRxKb0ruwa7ANGKPZ-z40Q-W_A3wDrVd1Zg</recordid><startdate>200211</startdate><enddate>200211</enddate><creator>Elberg, Gerard</creator><creator>Hipkin, R. William</creator><creator>Schonbrunn, Agnes</creator><general>Endocrine Society</general><general>Oxford University Press</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></search><sort><creationdate>200211</creationdate><title>Homologous and Heterologous Regulation of Somatostatin Receptor 2</title><author>Elberg, Gerard ; Hipkin, R. William ; Schonbrunn, Agnes</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c401t-5651e5371c744bcf74dc3108f868a554f7ecb6b7a136b112676c4a31f596921b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Adenylyl Cyclase Inhibitors</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Indoles - pharmacology</topic><topic>Octreotide - pharmacology</topic><topic>Pancreas</topic><topic>Phosphorylation</topic><topic>Protein Kinase C - metabolism</topic><topic>Rats</topic><topic>Receptors, Somatostatin - drug effects</topic><topic>Receptors, Somatostatin - genetics</topic><topic>Receptors, Somatostatin - metabolism</topic><topic>Somatostatin - pharmacology</topic><topic>Tetradecanoylphorbol Acetate - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elberg, Gerard</creatorcontrib><creatorcontrib>Hipkin, R. William</creatorcontrib><creatorcontrib>Schonbrunn, Agnes</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Elberg, Gerard</au><au>Hipkin, R. William</au><au>Schonbrunn, Agnes</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Homologous and Heterologous Regulation of Somatostatin Receptor 2</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2002-11</date><risdate>2002</risdate><volume>16</volume><issue>11</issue><spage>2502</spage><epage>2514</epage><pages>2502-2514</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>We previously demonstrated that phosphorylation of somatostatin receptor 2A (sst2A) is rapidly increased in transfected cells both by agonist and by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). Here, we investigate whether PKC-mediated receptor phosphorylation is involved in the homologous or heterologous regulation of endogenous sst2 receptors in AR42J pancreatic acinar cells upon stimulation by agonist or by cholecystokinin (CCK) or bombesin (BBS). Somatostatin, PMA, CCK, and BBS all increased sst2A receptor phosphorylation 5- to 10-fold within minutes. Somatostatin binding also caused rapid internalization of the ligand-receptor complex, and PMA, CCK, and BBS all stimulated this internalization further. Additionally, sst2 receptor-mediated inhibition of adenylyl cyclase was desensitized by all treatments. Somatostatin, as well as peptidic (SMS201–995) and nonpeptidic (L-779,976) sst2 receptor agonists increased the EC50 for somatostatin inhibition 20-fold. In contrast, pretreatment with BBS, CCK, or PMA caused a modest 2-fold increase in the EC50 for cyclase inhibition. Whereas the PKC inhibitor GF109203X abolished sst2A receptor phosphorylation by CCK, BBS, and PMA, it did not alter the effect of somatostatin, demonstrating that these reactions were catalyzed by different kinases. Consistent with a functional role for PKC-mediated receptor phosphorylation, GF109203X prevented PMA stimulation of sst2 receptor internalization. Surprisingly, however, GF109203X did not inhibit BBS and CCK stimulation of sst2A receptor endocytosis. These results demonstrate that homologous and heterologous hormones induce sst2A receptor phosphorylation by PKC-independent and -dependent mechanisms, respectively, and produce distinct effects on receptor signaling and internalization. In addition, the heterologous hormones also modulate sst2 receptor internalization by a novel mechanism that is independent of receptor phosphorylation.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>12403839</pmid><doi>10.1210/me.2002-0207</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adenylyl Cyclase Inhibitors Amides - pharmacology Animals Cell Line Indoles - pharmacology Octreotide - pharmacology Pancreas Phosphorylation Protein Kinase C - metabolism Rats Receptors, Somatostatin - drug effects Receptors, Somatostatin - genetics Receptors, Somatostatin - metabolism Somatostatin - pharmacology Tetradecanoylphorbol Acetate - pharmacology |
title | Homologous and Heterologous Regulation of Somatostatin Receptor 2 |
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