Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1
The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of...
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| Veröffentlicht in: | Stroke (1970) 2002-09, Vol.33 (9), p.2324-2328 |
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| container_title | Stroke (1970) |
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| creator | PLANT, Leigh D KEMP, Paul J PEERS, Chris HENDERSON, Zaineb PEARSON, Hush A |
| description | The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P |
| doi_str_mv | 10.1161/01.STR.0000027440.68031.B0 |
| format | Article |
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Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1-selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.</description><identifier>ISSN: 0039-2499</identifier><identifier>EISSN: 1524-4628</identifier><identifier>DOI: 10.1161/01.STR.0000027440.68031.B0</identifier><identifier>PMID: 12215606</identifier><identifier>CODEN: SJCCA7</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Acidosis - metabolism ; Animals ; Arachidonic Acids - pharmacology ; Biological and medical sciences ; Cell Hypoxia - drug effects ; Cell Hypoxia - physiology ; Cells, Cultured ; Endocannabinoids ; Hydrogen-Ion Concentration ; Medical sciences ; Membrane Potentials - drug effects ; Membrane Potentials - physiology ; Nerve Tissue Proteins - antagonists & inhibitors ; Neurology ; Neurons - cytology ; Neurons - drug effects ; Neurons - physiology ; Patch-Clamp Techniques ; Polyunsaturated Alkamides ; Potassium - metabolism ; Potassium Channel Blockers ; Potassium Channels ; Potassium Channels, Tandem Pore Domain ; Rats ; Vascular diseases and vascular malformations of the nervous system</subject><ispartof>Stroke (1970), 2002-09, Vol.33 (9), p.2324-2328</ispartof><rights>2002 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Sep 2002</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c465t-f0261ff29c9f5ce577915b4bbe90bdd2a44dafaf8545218712247532fbfb26333</citedby><cites>FETCH-LOGICAL-c465t-f0261ff29c9f5ce577915b4bbe90bdd2a44dafaf8545218712247532fbfb26333</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,3688,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=13920149$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12215606$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PLANT, Leigh D</creatorcontrib><creatorcontrib>KEMP, Paul J</creatorcontrib><creatorcontrib>PEERS, Chris</creatorcontrib><creatorcontrib>HENDERSON, Zaineb</creatorcontrib><creatorcontrib>PEARSON, Hush A</creatorcontrib><title>Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1</title><title>Stroke (1970)</title><addtitle>Stroke</addtitle><description>The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1-selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.</description><subject>Acidosis - metabolism</subject><subject>Animals</subject><subject>Arachidonic Acids - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Hypoxia - drug effects</subject><subject>Cell Hypoxia - physiology</subject><subject>Cells, Cultured</subject><subject>Endocannabinoids</subject><subject>Hydrogen-Ion Concentration</subject><subject>Medical sciences</subject><subject>Membrane Potentials - drug effects</subject><subject>Membrane Potentials - physiology</subject><subject>Nerve Tissue Proteins - antagonists & inhibitors</subject><subject>Neurology</subject><subject>Neurons - cytology</subject><subject>Neurons - drug effects</subject><subject>Neurons - physiology</subject><subject>Patch-Clamp Techniques</subject><subject>Polyunsaturated Alkamides</subject><subject>Potassium - metabolism</subject><subject>Potassium Channel Blockers</subject><subject>Potassium Channels</subject><subject>Potassium Channels, Tandem Pore Domain</subject><subject>Rats</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0039-2499</issn><issn>1524-4628</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkF1LHDEUhoO06Nb2L5RBaO9mmpOvmXinYmtREHS9DkkmqZHZyZjsQLe_3mxdWTA3B8LznvPyIHQCuAEQ8ANDc7-8a_D2kZYx3IgOU2jO8QFaACesZoJ0H9ACYyprwqQ8Qp9yftritOOH6AgIAS6wWKCHq80U_wZb9W6Kg07hn16HOFbRV9YlZ9xQPqs_SY_z4KrRzSmOuTKbKk_OBl-CYXwMJryFlmf31zV8Rh-9HrL7spvH6OHn5fLiqr65_fX74uymtkzwde0xEeA9kVZ6bh1vWwncMGOcxKbviWas1177jjNOoGtLbdZySrzxhghK6TH6_rp3SvF5dnmtViHbbefRxTmrlmAhOOcFPHkHPsU5jaWbAtm2RR9mBTp9hWyKOSfn1ZTCSqeNAqy25hUGVcyrvXn137w6xyX8dXdhNivX76M71QX4tgN0tnrwRakNec9RSTAwSV8AirSLlg</recordid><startdate>20020901</startdate><enddate>20020901</enddate><creator>PLANT, Leigh D</creator><creator>KEMP, Paul J</creator><creator>PEERS, Chris</creator><creator>HENDERSON, Zaineb</creator><creator>PEARSON, Hush A</creator><general>Lippincott Williams & Wilkins</general><general>American Heart Association, Inc</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>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20020901</creationdate><title>Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1</title><author>PLANT, Leigh D ; KEMP, Paul J ; PEERS, Chris ; HENDERSON, Zaineb ; PEARSON, Hush A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-f0261ff29c9f5ce577915b4bbe90bdd2a44dafaf8545218712247532fbfb26333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Acidosis - metabolism</topic><topic>Animals</topic><topic>Arachidonic Acids - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Hypoxia - drug effects</topic><topic>Cell Hypoxia - physiology</topic><topic>Cells, Cultured</topic><topic>Endocannabinoids</topic><topic>Hydrogen-Ion Concentration</topic><topic>Medical sciences</topic><topic>Membrane Potentials - drug effects</topic><topic>Membrane Potentials - physiology</topic><topic>Nerve Tissue Proteins - antagonists & inhibitors</topic><topic>Neurology</topic><topic>Neurons - cytology</topic><topic>Neurons - drug effects</topic><topic>Neurons - physiology</topic><topic>Patch-Clamp Techniques</topic><topic>Polyunsaturated Alkamides</topic><topic>Potassium - metabolism</topic><topic>Potassium Channel Blockers</topic><topic>Potassium Channels</topic><topic>Potassium Channels, Tandem Pore Domain</topic><topic>Rats</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PLANT, Leigh D</creatorcontrib><creatorcontrib>KEMP, Paul J</creatorcontrib><creatorcontrib>PEERS, Chris</creatorcontrib><creatorcontrib>HENDERSON, Zaineb</creatorcontrib><creatorcontrib>PEARSON, Hush A</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>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Stroke (1970)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PLANT, Leigh D</au><au>KEMP, Paul J</au><au>PEERS, Chris</au><au>HENDERSON, Zaineb</au><au>PEARSON, Hush A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1</atitle><jtitle>Stroke (1970)</jtitle><addtitle>Stroke</addtitle><date>2002-09-01</date><risdate>2002</risdate><volume>33</volume><issue>9</issue><spage>2324</spage><epage>2328</epage><pages>2324-2328</pages><issn>0039-2499</issn><eissn>1524-4628</eissn><coden>SJCCA7</coden><abstract>The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1-selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>12215606</pmid><doi>10.1161/01.STR.0000027440.68031.B0</doi><tpages>5</tpages></addata></record> |
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| source | MEDLINE; American Heart Association Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Journals@Ovid Complete; Alma/SFX Local Collection |
| subjects | Acidosis - metabolism Animals Arachidonic Acids - pharmacology Biological and medical sciences Cell Hypoxia - drug effects Cell Hypoxia - physiology Cells, Cultured Endocannabinoids Hydrogen-Ion Concentration Medical sciences Membrane Potentials - drug effects Membrane Potentials - physiology Nerve Tissue Proteins - antagonists & inhibitors Neurology Neurons - cytology Neurons - drug effects Neurons - physiology Patch-Clamp Techniques Polyunsaturated Alkamides Potassium - metabolism Potassium Channel Blockers Potassium Channels Potassium Channels, Tandem Pore Domain Rats Vascular diseases and vascular malformations of the nervous system |
| title | Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1 |
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