Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork
To determine the effects of inhibition of protein geranylgeranyltransferase type I (GGTase-I), which isoprenylates so-called CaaX proteins, including the GTP-binding proteins such as Rho GTPases and the betagamma subunits of heterotrimeric G-proteins, on aqueous humor outflow and trabecular meshwork...
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| Veröffentlicht in: | Investigative ophthalmology & visual science 2008-06, Vol.49 (6), p.2464-2471 |
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| creator | Rao, P. Vasantha Peterson, Yuri K Inoue, Toshihiro Casey, Patrick J |
| description | To determine the effects of inhibition of protein geranylgeranyltransferase type I (GGTase-I), which isoprenylates so-called CaaX proteins, including the GTP-binding proteins such as Rho GTPases and the betagamma subunits of heterotrimeric G-proteins, on aqueous humor outflow and trabecular meshwork cytoskeletal integrity.
A selective small molecular inhibitor of GGTase-I, GGTI-DU40, was tested in this study to investigate its effects on actin cytoskeletal integrity, cell adhesions, cell-cell junctions, myosin II phosphosphorylation, and membrane localization of GTP-binding proteins in trabecular meshwork (TM) cells, using immunofluorescence detection and immunoblotting analysis. The effects of GGTI-DU40 on aqueous humor outflow were determined using organ-cultured, perfused anterior segments of porcine eyes.
In the TM cell lysates, GGTI-DU40 was confirmed to inhibit GGTase-I activity in a dose-dependent manner. TM cells treated with GGTI-DU40 displayed dose-dependent changes in cell morphology and reversible decreases in actin stress fibers, focal adhesions, and adherens junctions. Myosin light chain phosphorylation was decreased significantly, and membrane localization of isoprenylated small GTPases and Gbetagamma was impaired in drug-treated TM cells. Aqueous outflow facility was increased significantly in eyes perfused with GGTI-DU40.
These data demonstrate that inhibition of geranylgeranyl isoprenylation of CaaX proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study indicates that the GGTase-I enzyme is a promising molecular target for lowering increased ocular pressure in glaucoma patients. |
| doi_str_mv | 10.1167/iovs.07-1639 |
| format | Article |
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A selective small molecular inhibitor of GGTase-I, GGTI-DU40, was tested in this study to investigate its effects on actin cytoskeletal integrity, cell adhesions, cell-cell junctions, myosin II phosphosphorylation, and membrane localization of GTP-binding proteins in trabecular meshwork (TM) cells, using immunofluorescence detection and immunoblotting analysis. The effects of GGTI-DU40 on aqueous humor outflow were determined using organ-cultured, perfused anterior segments of porcine eyes.
In the TM cell lysates, GGTI-DU40 was confirmed to inhibit GGTase-I activity in a dose-dependent manner. TM cells treated with GGTI-DU40 displayed dose-dependent changes in cell morphology and reversible decreases in actin stress fibers, focal adhesions, and adherens junctions. Myosin light chain phosphorylation was decreased significantly, and membrane localization of isoprenylated small GTPases and Gbetagamma was impaired in drug-treated TM cells. Aqueous outflow facility was increased significantly in eyes perfused with GGTI-DU40.
These data demonstrate that inhibition of geranylgeranyl isoprenylation of CaaX proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study indicates that the GGTase-I enzyme is a promising molecular target for lowering increased ocular pressure in glaucoma patients.</description><identifier>ISSN: 0146-0404</identifier><identifier>ISSN: 1552-5783</identifier><identifier>EISSN: 1552-5783</identifier><identifier>DOI: 10.1167/iovs.07-1639</identifier><identifier>PMID: 18316706</identifier><identifier>CODEN: IOVSDA</identifier><language>eng</language><publisher>Rockville, MD: ARVO</publisher><subject>Actins - metabolism ; Adherens Junctions - metabolism ; Alkyl and Aryl Transferases - antagonists & inhibitors ; Alkyl and Aryl Transferases - metabolism ; Animals ; Aqueous Humor - secretion ; Biological and medical sciences ; Cell Adhesion - drug effects ; Cell Shape - drug effects ; Cells, Cultured ; Dose-Response Relationship, Drug ; Enzyme Inhibitors - pharmacology ; Eye and associated structures. Visual pathways and centers. Vision ; Focal Adhesions - metabolism ; Fundamental and applied biological sciences. Psychology ; Intercellular Junctions - drug effects ; Medical sciences ; Microscopy, Phase-Contrast ; Monomeric GTP-Binding Proteins - metabolism ; Myosin Light Chains - metabolism ; Myosin Type II - metabolism ; Ophthalmology ; Organ Culture Techniques ; Phosphorylation ; Protein Prenylation ; Pyrazoles - pharmacology ; Pyridines - pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Swine ; Time Factors ; Trabecular Meshwork - drug effects ; Trabecular Meshwork - enzymology ; Vertebrates: nervous system and sense organs</subject><ispartof>Investigative ophthalmology & visual science, 2008-06, Vol.49 (6), p.2464-2471</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-720b18d123e655f690077c717347061f5001fe4a59dc99eb3b4adf96438835023</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561264/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2561264/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20406064$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18316706$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rao, P. Vasantha</creatorcontrib><creatorcontrib>Peterson, Yuri K</creatorcontrib><creatorcontrib>Inoue, Toshihiro</creatorcontrib><creatorcontrib>Casey, Patrick J</creatorcontrib><title>Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork</title><title>Investigative ophthalmology & visual science</title><addtitle>Invest Ophthalmol Vis Sci</addtitle><description>To determine the effects of inhibition of protein geranylgeranyltransferase type I (GGTase-I), which isoprenylates so-called CaaX proteins, including the GTP-binding proteins such as Rho GTPases and the betagamma subunits of heterotrimeric G-proteins, on aqueous humor outflow and trabecular meshwork cytoskeletal integrity.
A selective small molecular inhibitor of GGTase-I, GGTI-DU40, was tested in this study to investigate its effects on actin cytoskeletal integrity, cell adhesions, cell-cell junctions, myosin II phosphosphorylation, and membrane localization of GTP-binding proteins in trabecular meshwork (TM) cells, using immunofluorescence detection and immunoblotting analysis. The effects of GGTI-DU40 on aqueous humor outflow were determined using organ-cultured, perfused anterior segments of porcine eyes.
In the TM cell lysates, GGTI-DU40 was confirmed to inhibit GGTase-I activity in a dose-dependent manner. TM cells treated with GGTI-DU40 displayed dose-dependent changes in cell morphology and reversible decreases in actin stress fibers, focal adhesions, and adherens junctions. Myosin light chain phosphorylation was decreased significantly, and membrane localization of isoprenylated small GTPases and Gbetagamma was impaired in drug-treated TM cells. Aqueous outflow facility was increased significantly in eyes perfused with GGTI-DU40.
These data demonstrate that inhibition of geranylgeranyl isoprenylation of CaaX proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study indicates that the GGTase-I enzyme is a promising molecular target for lowering increased ocular pressure in glaucoma patients.</description><subject>Actins - metabolism</subject><subject>Adherens Junctions - metabolism</subject><subject>Alkyl and Aryl Transferases - antagonists & inhibitors</subject><subject>Alkyl and Aryl Transferases - metabolism</subject><subject>Animals</subject><subject>Aqueous Humor - secretion</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Shape - drug effects</subject><subject>Cells, Cultured</subject><subject>Dose-Response Relationship, Drug</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Eye and associated structures. Visual pathways and centers. Vision</subject><subject>Focal Adhesions - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Intercellular Junctions - drug effects</subject><subject>Medical sciences</subject><subject>Microscopy, Phase-Contrast</subject><subject>Monomeric GTP-Binding Proteins - metabolism</subject><subject>Myosin Light Chains - metabolism</subject><subject>Myosin Type II - metabolism</subject><subject>Ophthalmology</subject><subject>Organ Culture Techniques</subject><subject>Phosphorylation</subject><subject>Protein Prenylation</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Swine</subject><subject>Time Factors</subject><subject>Trabecular Meshwork - drug effects</subject><subject>Trabecular Meshwork - enzymology</subject><subject>Vertebrates: nervous system and sense organs</subject><issn>0146-0404</issn><issn>1552-5783</issn><issn>1552-5783</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUFv1DAQhS0EosvCjTPyBU6kjO3YTi5IVVXalYrKoZwtx2snhiRe7KTR_gN-Nt7uqsDFz9J880YzD6G3BM4JEfKTDw_pHGRBBKufoRXhnBZcVuw5WgEpRQEllGfoVUo_ACghFF6iM1Kx3ApihX5fOWfNlHBw-Fun46BN6EPrDd6MnW_85MP4WIthsn7E1zbqcd-3R5nym1z-J4vv9zuLNzjjF79mG-aEb-YhRHw3T64PC566GOa2y5rZqBtr5l5H_NWmbgnx52v0wuk-2TcnXaPvX67uL2-K27vrzeXFbWE41FMhKTSk2hLKrODciRpASiOJZGXehzgOQJwtNa-3pq5tw5pSb10tSlZVjANla_T56Lubm8FujR3zEr3aRT_ouFdBe_V_ZfSdasODolwQmn3W6OPRwMSQUrTuqZeAOiSiDokokOqQSMbf_TvvL3yKIAPvT4BORvcun9T49MTRnJ-Ax7kfjlzn227x0ao06L7PtkQty1LWSihaZvAPluilAg</recordid><startdate>20080601</startdate><enddate>20080601</enddate><creator>Rao, P. Vasantha</creator><creator>Peterson, Yuri K</creator><creator>Inoue, Toshihiro</creator><creator>Casey, Patrick J</creator><general>ARVO</general><general>Association for Research in Vision and Ophtalmology</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>5PM</scope></search><sort><creationdate>20080601</creationdate><title>Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork</title><author>Rao, P. Vasantha ; Peterson, Yuri K ; Inoue, Toshihiro ; Casey, Patrick J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-720b18d123e655f690077c717347061f5001fe4a59dc99eb3b4adf96438835023</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Actins - metabolism</topic><topic>Adherens Junctions - metabolism</topic><topic>Alkyl and Aryl Transferases - antagonists & inhibitors</topic><topic>Alkyl and Aryl Transferases - metabolism</topic><topic>Animals</topic><topic>Aqueous Humor - secretion</topic><topic>Biological and medical sciences</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Shape - drug effects</topic><topic>Cells, Cultured</topic><topic>Dose-Response Relationship, Drug</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Eye and associated structures. Visual pathways and centers. Vision</topic><topic>Focal Adhesions - metabolism</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Intercellular Junctions - drug effects</topic><topic>Medical sciences</topic><topic>Microscopy, Phase-Contrast</topic><topic>Monomeric GTP-Binding Proteins - metabolism</topic><topic>Myosin Light Chains - metabolism</topic><topic>Myosin Type II - metabolism</topic><topic>Ophthalmology</topic><topic>Organ Culture Techniques</topic><topic>Phosphorylation</topic><topic>Protein Prenylation</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Swine</topic><topic>Time Factors</topic><topic>Trabecular Meshwork - drug effects</topic><topic>Trabecular Meshwork - enzymology</topic><topic>Vertebrates: nervous system and sense organs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rao, P. Vasantha</creatorcontrib><creatorcontrib>Peterson, Yuri K</creatorcontrib><creatorcontrib>Inoue, Toshihiro</creatorcontrib><creatorcontrib>Casey, Patrick J</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>PubMed Central (Full Participant titles)</collection><jtitle>Investigative ophthalmology & visual science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rao, P. Vasantha</au><au>Peterson, Yuri K</au><au>Inoue, Toshihiro</au><au>Casey, Patrick J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork</atitle><jtitle>Investigative ophthalmology & visual science</jtitle><addtitle>Invest Ophthalmol Vis Sci</addtitle><date>2008-06-01</date><risdate>2008</risdate><volume>49</volume><issue>6</issue><spage>2464</spage><epage>2471</epage><pages>2464-2471</pages><issn>0146-0404</issn><issn>1552-5783</issn><eissn>1552-5783</eissn><coden>IOVSDA</coden><abstract>To determine the effects of inhibition of protein geranylgeranyltransferase type I (GGTase-I), which isoprenylates so-called CaaX proteins, including the GTP-binding proteins such as Rho GTPases and the betagamma subunits of heterotrimeric G-proteins, on aqueous humor outflow and trabecular meshwork cytoskeletal integrity.
A selective small molecular inhibitor of GGTase-I, GGTI-DU40, was tested in this study to investigate its effects on actin cytoskeletal integrity, cell adhesions, cell-cell junctions, myosin II phosphosphorylation, and membrane localization of GTP-binding proteins in trabecular meshwork (TM) cells, using immunofluorescence detection and immunoblotting analysis. The effects of GGTI-DU40 on aqueous humor outflow were determined using organ-cultured, perfused anterior segments of porcine eyes.
In the TM cell lysates, GGTI-DU40 was confirmed to inhibit GGTase-I activity in a dose-dependent manner. TM cells treated with GGTI-DU40 displayed dose-dependent changes in cell morphology and reversible decreases in actin stress fibers, focal adhesions, and adherens junctions. Myosin light chain phosphorylation was decreased significantly, and membrane localization of isoprenylated small GTPases and Gbetagamma was impaired in drug-treated TM cells. Aqueous outflow facility was increased significantly in eyes perfused with GGTI-DU40.
These data demonstrate that inhibition of geranylgeranyl isoprenylation of CaaX proteins in the aqueous outflow pathway increases aqueous humor outflow, possibly through altered cell adhesive interactions and actin cytoskeletal organization in cells of the outflow pathway. This study indicates that the GGTase-I enzyme is a promising molecular target for lowering increased ocular pressure in glaucoma patients.</abstract><cop>Rockville, MD</cop><pub>ARVO</pub><pmid>18316706</pmid><doi>10.1167/iovs.07-1639</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Actins - metabolism Adherens Junctions - metabolism Alkyl and Aryl Transferases - antagonists & inhibitors Alkyl and Aryl Transferases - metabolism Animals Aqueous Humor - secretion Biological and medical sciences Cell Adhesion - drug effects Cell Shape - drug effects Cells, Cultured Dose-Response Relationship, Drug Enzyme Inhibitors - pharmacology Eye and associated structures. Visual pathways and centers. Vision Focal Adhesions - metabolism Fundamental and applied biological sciences. Psychology Intercellular Junctions - drug effects Medical sciences Microscopy, Phase-Contrast Monomeric GTP-Binding Proteins - metabolism Myosin Light Chains - metabolism Myosin Type II - metabolism Ophthalmology Organ Culture Techniques Phosphorylation Protein Prenylation Pyrazoles - pharmacology Pyridines - pharmacology Reverse Transcriptase Polymerase Chain Reaction Swine Time Factors Trabecular Meshwork - drug effects Trabecular Meshwork - enzymology Vertebrates: nervous system and sense organs |
| title | Effects of Pharmacologic Inhibition of Protein Geranylgeranyltransferase Type I on Aqueous Humor Outflow through the Trabecular Meshwork |
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