Inhibition of Glial Cell Line‐Derived Neurotrophic Factor Induced Intracellular Activity by K‐252b on Dopaminergic Neurons
: The c‐ret protooncogene encodes Ret, the functional tyrosine kinase receptor for glial cell line‐derived neurotrophic factor (GDNF). K‐252b, a known protein tyrosine kinase inhibitor, has been shown earlier to inhibit the trophic activity of brain‐derived neurotrophic factor on dopaminergic (DAerg...
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| Veröffentlicht in: | Journal of neurochemistry 1997-09, Vol.69 (3), p.986-994 |
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| creator | Pong, Kevin Xu, Ren Y. Beck, Klaus D. Zhang, T. J. Louis, Jean‐Claude |
| description | : The c‐ret protooncogene encodes Ret, the functional tyrosine kinase receptor for glial cell line‐derived neurotrophic factor (GDNF). K‐252b, a known protein tyrosine kinase inhibitor, has been shown earlier to inhibit the trophic activity of brain‐derived neurotrophic factor on dopaminergic (DAergic) neurons and nerve growth factor on basal forebrain cholinergic neurons while potentiating neurotrophin‐3 activity on central cholinergic and peripheral sensory neurons and PC12 cells. We tested whether K‐252b would modulate GDNF‐induced differentiation in DAergic neuron cultures. Exposure to 1 ng/ml GDNF increased dopamine (DA) uptake 80% above control, whereas treatment with 5 µM K‐252b decreased the efficacy of GDNF by 60%. Concentrations of GDNF of 100 pg/ml were moderately active, between 10 and 20% above control. In addition, K‐252b shifted the ED50 from 20 to 200 pg/ml. GDNF treatment increased soma size and neurite outgrowth in tyrosine hydroxylase‐immunoreactive neurons. K‐252b inhibited differentiation of these morphological parameters induced by GDNF. Furthermore, GDNF stimulated Ret autophosphorylation at maximal levels, whereas the inhibition of DA uptake and morphological differentiation by K‐252b correlated with a significantly decreased level of Ret autophosphorylation. Therefore, K‐252b is able to inhibit intracellular activities induced by GDNF on mesencephalic DAergic neurons. |
| doi_str_mv | 10.1046/j.1471-4159.1997.69030986.x |
| format | Article |
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J. ; Louis, Jean‐Claude</creator><creatorcontrib>Pong, Kevin ; Xu, Ren Y. ; Beck, Klaus D. ; Zhang, T. J. ; Louis, Jean‐Claude</creatorcontrib><description>: The c‐ret protooncogene encodes Ret, the functional tyrosine kinase receptor for glial cell line‐derived neurotrophic factor (GDNF). K‐252b, a known protein tyrosine kinase inhibitor, has been shown earlier to inhibit the trophic activity of brain‐derived neurotrophic factor on dopaminergic (DAergic) neurons and nerve growth factor on basal forebrain cholinergic neurons while potentiating neurotrophin‐3 activity on central cholinergic and peripheral sensory neurons and PC12 cells. We tested whether K‐252b would modulate GDNF‐induced differentiation in DAergic neuron cultures. Exposure to 1 ng/ml GDNF increased dopamine (DA) uptake 80% above control, whereas treatment with 5 µM K‐252b decreased the efficacy of GDNF by 60%. Concentrations of GDNF of <100 pg/ml were completely inhibited, whereas concentrations of >100 pg/ml were moderately active, between 10 and 20% above control. In addition, K‐252b shifted the ED50 from 20 to 200 pg/ml. GDNF treatment increased soma size and neurite outgrowth in tyrosine hydroxylase‐immunoreactive neurons. K‐252b inhibited differentiation of these morphological parameters induced by GDNF. Furthermore, GDNF stimulated Ret autophosphorylation at maximal levels, whereas the inhibition of DA uptake and morphological differentiation by K‐252b correlated with a significantly decreased level of Ret autophosphorylation. Therefore, K‐252b is able to inhibit intracellular activities induced by GDNF on mesencephalic DAergic neurons.</description><identifier>ISSN: 0022-3042</identifier><identifier>EISSN: 1471-4159</identifier><identifier>DOI: 10.1046/j.1471-4159.1997.69030986.x</identifier><identifier>PMID: 9282920</identifier><identifier>CODEN: JONRA9</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Science Ltd</publisher><subject>Animals ; Biological and medical sciences ; Biological Transport - drug effects ; Carbazoles - pharmacology ; Cell Differentiation ; Cells, Cultured ; Dopamine - metabolism ; Dopaminergic neurons ; Drosophila Proteins ; Enzyme Inhibitors - pharmacology ; Fetus ; Fundamental and applied biological sciences. Psychology ; Glial Cell Line-Derived Neurotrophic Factor ; Glial Cell Line-Derived Neurotrophic Factor Receptors ; Humans ; Indole Alkaloids ; Isolated neuron and nerve. Neuroglia ; Kinetics ; K‐252b ; Mesencephalon - metabolism ; Nerve Growth Factors ; Nerve Tissue Proteins - antagonists & inhibitors ; Nerve Tissue Proteins - pharmacology ; Neurons - cytology ; Neurons - drug effects ; Neurons - metabolism ; Neuroprotective Agents - pharmacology ; Neurotrophic factors ; Phosphorylation ; Protein Kinase C - antagonists & inhibitors ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-ret ; Rats ; Rats, Sprague-Dawley ; Receptor Protein-Tyrosine Kinases - metabolism ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - pharmacology ; Ret protein tyrosine kinase ; Tyrosine 3-Monooxygenase - analysis ; Vertebrates: nervous system and sense organs</subject><ispartof>Journal of neurochemistry, 1997-09, Vol.69 (3), p.986-994</ispartof><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5256-80fa3e5c41fe1bafa0e810fd21ae0c2c4c14fbada7c87add20ebb716d1541d883</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1046%2Fj.1471-4159.1997.69030986.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1046%2Fj.1471-4159.1997.69030986.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,1434,27929,27930,45579,45580,46414,46838</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2780727$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9282920$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pong, Kevin</creatorcontrib><creatorcontrib>Xu, Ren Y.</creatorcontrib><creatorcontrib>Beck, Klaus D.</creatorcontrib><creatorcontrib>Zhang, T. J.</creatorcontrib><creatorcontrib>Louis, Jean‐Claude</creatorcontrib><title>Inhibition of Glial Cell Line‐Derived Neurotrophic Factor Induced Intracellular Activity by K‐252b on Dopaminergic Neurons</title><title>Journal of neurochemistry</title><addtitle>J Neurochem</addtitle><description>: The c‐ret protooncogene encodes Ret, the functional tyrosine kinase receptor for glial cell line‐derived neurotrophic factor (GDNF). K‐252b, a known protein tyrosine kinase inhibitor, has been shown earlier to inhibit the trophic activity of brain‐derived neurotrophic factor on dopaminergic (DAergic) neurons and nerve growth factor on basal forebrain cholinergic neurons while potentiating neurotrophin‐3 activity on central cholinergic and peripheral sensory neurons and PC12 cells. We tested whether K‐252b would modulate GDNF‐induced differentiation in DAergic neuron cultures. Exposure to 1 ng/ml GDNF increased dopamine (DA) uptake 80% above control, whereas treatment with 5 µM K‐252b decreased the efficacy of GDNF by 60%. Concentrations of GDNF of <100 pg/ml were completely inhibited, whereas concentrations of >100 pg/ml were moderately active, between 10 and 20% above control. In addition, K‐252b shifted the ED50 from 20 to 200 pg/ml. GDNF treatment increased soma size and neurite outgrowth in tyrosine hydroxylase‐immunoreactive neurons. K‐252b inhibited differentiation of these morphological parameters induced by GDNF. Furthermore, GDNF stimulated Ret autophosphorylation at maximal levels, whereas the inhibition of DA uptake and morphological differentiation by K‐252b correlated with a significantly decreased level of Ret autophosphorylation. Therefore, K‐252b is able to inhibit intracellular activities induced by GDNF on mesencephalic DAergic neurons.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Transport - drug effects</subject><subject>Carbazoles - pharmacology</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Dopamine - metabolism</subject><subject>Dopaminergic neurons</subject><subject>Drosophila Proteins</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Fetus</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glial Cell Line-Derived Neurotrophic Factor</subject><subject>Glial Cell Line-Derived Neurotrophic Factor Receptors</subject><subject>Humans</subject><subject>Indole Alkaloids</subject><subject>Isolated neuron and nerve. Neuroglia</subject><subject>Kinetics</subject><subject>K‐252b</subject><subject>Mesencephalon - metabolism</subject><subject>Nerve Growth Factors</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Nerve Tissue Proteins - pharmacology</subject><subject>Neurons - cytology</subject><subject>Neurons - drug effects</subject><subject>Neurons - metabolism</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neurotrophic factors</subject><subject>Phosphorylation</subject><subject>Protein Kinase C - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-ret</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptor Protein-Tyrosine Kinases - metabolism</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - pharmacology</subject><subject>Ret protein tyrosine kinase</subject><subject>Tyrosine 3-Monooxygenase - analysis</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0022-3042</issn><issn>1471-4159</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkM1u1DAURi1EVaaFR0CyBGKX9Npx4kSsqhnaDozKBtaW4x_qUSYe7KR0NqiPwDPyJHWY6exZWVffd4-vDkLvCOQEWHWxzgnjJGOkbHLSNDyvGiigqav84QWaHbOXaAZAaVYAo6_QWYxrAFKxipyi04bWtKEwQ7-X_Z1r3eB8j73F152THZ6brsMr15u_j38WJrh7o_GtGYMfgt_eOYWvpBp8wMtejyply34IUqWlsZMBX6rB3bthh9sd_pIItKQtTviF38pNgoYfifAP18fX6MTKLpo3h_ccfb_69G1-k62-Xi_nl6tMlbSsshqsLEypGLGGtNJKMDUBqymRBhRVTBFmW6klVzWXWlMwbctJpUnJiK7r4hx92HO3wf8cTRzExsXpYtkbP0bBG1pyKCEVP-6LKvgYg7FiG9xGhp0gICb7Yi0mw2IyLCb74tm-eEjbbw_fjO3G6OPuQXfK3x9yGZXsbJC9cvFYo7wGTnmqLfa1X64zu_-5QHy-nT9PxRO8sqWm</recordid><startdate>199709</startdate><enddate>199709</enddate><creator>Pong, Kevin</creator><creator>Xu, Ren Y.</creator><creator>Beck, Klaus D.</creator><creator>Zhang, T. J.</creator><creator>Louis, Jean‐Claude</creator><general>Blackwell Science Ltd</general><general>Blackwell</general><scope>IQODW</scope><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></search><sort><creationdate>199709</creationdate><title>Inhibition of Glial Cell Line‐Derived Neurotrophic Factor Induced Intracellular Activity by K‐252b on Dopaminergic Neurons</title><author>Pong, Kevin ; Xu, Ren Y. ; Beck, Klaus D. ; Zhang, T. J. ; Louis, Jean‐Claude</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5256-80fa3e5c41fe1bafa0e810fd21ae0c2c4c14fbada7c87add20ebb716d1541d883</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Transport - drug effects</topic><topic>Carbazoles - pharmacology</topic><topic>Cell Differentiation</topic><topic>Cells, Cultured</topic><topic>Dopamine - metabolism</topic><topic>Dopaminergic neurons</topic><topic>Drosophila Proteins</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Fetus</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Glial Cell Line-Derived Neurotrophic Factor</topic><topic>Glial Cell Line-Derived Neurotrophic Factor Receptors</topic><topic>Humans</topic><topic>Indole Alkaloids</topic><topic>Isolated neuron and nerve. Neuroglia</topic><topic>Kinetics</topic><topic>K‐252b</topic><topic>Mesencephalon - metabolism</topic><topic>Nerve Growth Factors</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Nerve Tissue Proteins - pharmacology</topic><topic>Neurons - cytology</topic><topic>Neurons - drug effects</topic><topic>Neurons - metabolism</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neurotrophic factors</topic><topic>Phosphorylation</topic><topic>Protein Kinase C - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-ret</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptor Protein-Tyrosine Kinases - metabolism</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Ret protein tyrosine kinase</topic><topic>Tyrosine 3-Monooxygenase - analysis</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pong, Kevin</creatorcontrib><creatorcontrib>Xu, Ren Y.</creatorcontrib><creatorcontrib>Beck, Klaus D.</creatorcontrib><creatorcontrib>Zhang, T. J.</creatorcontrib><creatorcontrib>Louis, Jean‐Claude</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Journal of neurochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pong, Kevin</au><au>Xu, Ren Y.</au><au>Beck, Klaus D.</au><au>Zhang, T. J.</au><au>Louis, Jean‐Claude</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Glial Cell Line‐Derived Neurotrophic Factor Induced Intracellular Activity by K‐252b on Dopaminergic Neurons</atitle><jtitle>Journal of neurochemistry</jtitle><addtitle>J Neurochem</addtitle><date>1997-09</date><risdate>1997</risdate><volume>69</volume><issue>3</issue><spage>986</spage><epage>994</epage><pages>986-994</pages><issn>0022-3042</issn><eissn>1471-4159</eissn><coden>JONRA9</coden><abstract>: The c‐ret protooncogene encodes Ret, the functional tyrosine kinase receptor for glial cell line‐derived neurotrophic factor (GDNF). K‐252b, a known protein tyrosine kinase inhibitor, has been shown earlier to inhibit the trophic activity of brain‐derived neurotrophic factor on dopaminergic (DAergic) neurons and nerve growth factor on basal forebrain cholinergic neurons while potentiating neurotrophin‐3 activity on central cholinergic and peripheral sensory neurons and PC12 cells. We tested whether K‐252b would modulate GDNF‐induced differentiation in DAergic neuron cultures. Exposure to 1 ng/ml GDNF increased dopamine (DA) uptake 80% above control, whereas treatment with 5 µM K‐252b decreased the efficacy of GDNF by 60%. Concentrations of GDNF of <100 pg/ml were completely inhibited, whereas concentrations of >100 pg/ml were moderately active, between 10 and 20% above control. In addition, K‐252b shifted the ED50 from 20 to 200 pg/ml. GDNF treatment increased soma size and neurite outgrowth in tyrosine hydroxylase‐immunoreactive neurons. K‐252b inhibited differentiation of these morphological parameters induced by GDNF. Furthermore, GDNF stimulated Ret autophosphorylation at maximal levels, whereas the inhibition of DA uptake and morphological differentiation by K‐252b correlated with a significantly decreased level of Ret autophosphorylation. Therefore, K‐252b is able to inhibit intracellular activities induced by GDNF on mesencephalic DAergic neurons.</abstract><cop>Oxford, UK</cop><pub>Blackwell Science Ltd</pub><pmid>9282920</pmid><doi>10.1046/j.1471-4159.1997.69030986.x</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological and medical sciences Biological Transport - drug effects Carbazoles - pharmacology Cell Differentiation Cells, Cultured Dopamine - metabolism Dopaminergic neurons Drosophila Proteins Enzyme Inhibitors - pharmacology Fetus Fundamental and applied biological sciences. Psychology Glial Cell Line-Derived Neurotrophic Factor Glial Cell Line-Derived Neurotrophic Factor Receptors Humans Indole Alkaloids Isolated neuron and nerve. Neuroglia Kinetics K‐252b Mesencephalon - metabolism Nerve Growth Factors Nerve Tissue Proteins - antagonists & inhibitors Nerve Tissue Proteins - pharmacology Neurons - cytology Neurons - drug effects Neurons - metabolism Neuroprotective Agents - pharmacology Neurotrophic factors Phosphorylation Protein Kinase C - antagonists & inhibitors Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-ret Rats Rats, Sprague-Dawley Receptor Protein-Tyrosine Kinases - metabolism Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - pharmacology Ret protein tyrosine kinase Tyrosine 3-Monooxygenase - analysis Vertebrates: nervous system and sense organs |
| title | Inhibition of Glial Cell Line‐Derived Neurotrophic Factor Induced Intracellular Activity by K‐252b on Dopaminergic Neurons |
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