New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel
Ca(v)beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alph...
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| Veröffentlicht in: | The Journal of biological chemistry 2008-06, Vol.283 (23), p.15577 |
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| creator | Lao, Qi Zong Kobrinsky, Evgeny Harry, Jo Beth Ravindran, Arippa Soldatov, Nikolai M |
| description | Ca(v)beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca(v)beta(2) subunit splice variants differentially modulate inactivation of Ca(2+) currents (I(Ca)). Previously we described beta(2Deltag), a functionally active splice variant of human Ca(v)beta(2) lacking MAGUK. By deletion analysis of beta(2Deltag), we have now identified a 41-amino acid C-terminal essential determinant (beta(2)CED) that stimulates I(Ca) in the absence of Ca(v)beta subunits and conveys a +20-mV shift in the peak of the I(Ca)-voltage relationship. The beta(2)CED is targeted by alpha(1C) to the plasma membrane, forms a complex with alpha(1C) but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the alpha(1C) subunit C terminus as a functionally relevant beta(2)CED binding site. The beta(2)CED interacts with LA/IQ in a Ca(2+)- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca(v)beta(2)/alpha(1C) interactions is sufficient to support I(Ca). However, beta(2)CED does not support Ca(2+)-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca(2+)-induced inactivation. The beta(2)CED is conserved only in Ca(v)beta(2) subunits. Thus, beta(2)CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca(v)beta(2)-subunit differential modulation of the Ca(v)1.2 calcium channel that in beta(2Deltag) occurs without MAGUK. |
| doi_str_mv | 10.1074/jbc.M802035200 |
| format | Article |
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The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca(v)beta(2) subunit splice variants differentially modulate inactivation of Ca(2+) currents (I(Ca)). Previously we described beta(2Deltag), a functionally active splice variant of human Ca(v)beta(2) lacking MAGUK. By deletion analysis of beta(2Deltag), we have now identified a 41-amino acid C-terminal essential determinant (beta(2)CED) that stimulates I(Ca) in the absence of Ca(v)beta subunits and conveys a +20-mV shift in the peak of the I(Ca)-voltage relationship. The beta(2)CED is targeted by alpha(1C) to the plasma membrane, forms a complex with alpha(1C) but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the alpha(1C) subunit C terminus as a functionally relevant beta(2)CED binding site. The beta(2)CED interacts with LA/IQ in a Ca(2+)- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca(v)beta(2)/alpha(1C) interactions is sufficient to support I(Ca). However, beta(2)CED does not support Ca(2+)-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca(2+)-induced inactivation. The beta(2)CED is conserved only in Ca(v)beta(2) subunits. Thus, beta(2)CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca(v)beta(2)-subunit differential modulation of the Ca(v)1.2 calcium channel that in beta(2Deltag) occurs without MAGUK.</description><identifier>ISSN: 0021-9258</identifier><identifier>DOI: 10.1074/jbc.M802035200</identifier><identifier>PMID: 18411278</identifier><language>eng</language><publisher>United States</publisher><subject>Amino Acid Motifs - physiology ; Amino Acid Sequence - genetics ; Binding Sites - physiology ; Calcium - metabolism ; Calcium Channels, L-Type - genetics ; Calcium Channels, L-Type - metabolism ; Calmodulin - genetics ; Calmodulin - metabolism ; Cell Line ; Cell Membrane - genetics ; Cell Membrane - metabolism ; Humans ; Ion Channel Gating - physiology ; Membrane Potentials - physiology ; Myocardium - metabolism ; Protein Structure, Tertiary - physiology ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Sequence Deletion</subject><ispartof>The Journal of biological chemistry, 2008-06, Vol.283 (23), p.15577</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18411278$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lao, Qi Zong</creatorcontrib><creatorcontrib>Kobrinsky, Evgeny</creatorcontrib><creatorcontrib>Harry, Jo Beth</creatorcontrib><creatorcontrib>Ravindran, Arippa</creatorcontrib><creatorcontrib>Soldatov, Nikolai M</creatorcontrib><title>New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Ca(v)beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca(v)beta(2) subunit splice variants differentially modulate inactivation of Ca(2+) currents (I(Ca)). Previously we described beta(2Deltag), a functionally active splice variant of human Ca(v)beta(2) lacking MAGUK. By deletion analysis of beta(2Deltag), we have now identified a 41-amino acid C-terminal essential determinant (beta(2)CED) that stimulates I(Ca) in the absence of Ca(v)beta subunits and conveys a +20-mV shift in the peak of the I(Ca)-voltage relationship. The beta(2)CED is targeted by alpha(1C) to the plasma membrane, forms a complex with alpha(1C) but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the alpha(1C) subunit C terminus as a functionally relevant beta(2)CED binding site. The beta(2)CED interacts with LA/IQ in a Ca(2+)- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca(v)beta(2)/alpha(1C) interactions is sufficient to support I(Ca). However, beta(2)CED does not support Ca(2+)-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca(2+)-induced inactivation. The beta(2)CED is conserved only in Ca(v)beta(2) subunits. Thus, beta(2)CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca(v)beta(2)-subunit differential modulation of the Ca(v)1.2 calcium channel that in beta(2Deltag) occurs without MAGUK.</description><subject>Amino Acid Motifs - physiology</subject><subject>Amino Acid Sequence - genetics</subject><subject>Binding Sites - physiology</subject><subject>Calcium - metabolism</subject><subject>Calcium Channels, L-Type - genetics</subject><subject>Calcium Channels, L-Type - metabolism</subject><subject>Calmodulin - genetics</subject><subject>Calmodulin - metabolism</subject><subject>Cell Line</subject><subject>Cell Membrane - genetics</subject><subject>Cell Membrane - metabolism</subject><subject>Humans</subject><subject>Ion Channel Gating - physiology</subject><subject>Membrane Potentials - physiology</subject><subject>Myocardium - metabolism</subject><subject>Protein Structure, Tertiary - physiology</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Sequence Deletion</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo1z8tKxDAYBeAsFGcc3bqUvEBrrk2ylHqFUREGt8OfG9OhTUubIr69BZ2zOZuPAwehG0pKSpS4O1pXvmnCCJeMkDO0JoTRwjCpV-hymo5kiTD0Aq2oFpQypdfo8z1844eQw9g1CVLGsR9xPgRcw5cNGRieZjunJuOu93MLuekT7uOJ0JJhB61r5g67A6QU2it0HqGdwvV_b9Du6XFXvxTbj-fX-n5bDFLowrpoKuEjMKCacyMhMkkq76xwwVWxktQLUAYquyAVgqdOSR4MV9YsjG_Q7d_sMNsu-P0wNh2MP_vTNf4LaZFPHA</recordid><startdate>20080606</startdate><enddate>20080606</enddate><creator>Lao, Qi Zong</creator><creator>Kobrinsky, Evgeny</creator><creator>Harry, Jo Beth</creator><creator>Ravindran, Arippa</creator><creator>Soldatov, Nikolai M</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20080606</creationdate><title>New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel</title><author>Lao, Qi Zong ; Kobrinsky, Evgeny ; Harry, Jo Beth ; Ravindran, Arippa ; Soldatov, Nikolai M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p548-bcf964dfa2a183395af2506dcb4cec6f651d4a79a6bdfa7eed1c753e937b96dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Amino Acid Motifs - physiology</topic><topic>Amino Acid Sequence - genetics</topic><topic>Binding Sites - physiology</topic><topic>Calcium - metabolism</topic><topic>Calcium Channels, L-Type - genetics</topic><topic>Calcium Channels, L-Type - metabolism</topic><topic>Calmodulin - genetics</topic><topic>Calmodulin - metabolism</topic><topic>Cell Line</topic><topic>Cell Membrane - genetics</topic><topic>Cell Membrane - metabolism</topic><topic>Humans</topic><topic>Ion Channel Gating - physiology</topic><topic>Membrane Potentials - physiology</topic><topic>Myocardium - metabolism</topic><topic>Protein Structure, Tertiary - physiology</topic><topic>Protein Subunits - genetics</topic><topic>Protein Subunits - metabolism</topic><topic>Sequence Deletion</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lao, Qi Zong</creatorcontrib><creatorcontrib>Kobrinsky, Evgeny</creatorcontrib><creatorcontrib>Harry, Jo Beth</creatorcontrib><creatorcontrib>Ravindran, Arippa</creatorcontrib><creatorcontrib>Soldatov, Nikolai M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lao, Qi Zong</au><au>Kobrinsky, Evgeny</au><au>Harry, Jo Beth</au><au>Ravindran, Arippa</au><au>Soldatov, Nikolai M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2008-06-06</date><risdate>2008</risdate><volume>283</volume><issue>23</issue><spage>15577</spage><pages>15577-</pages><issn>0021-9258</issn><abstract>Ca(v)beta subunits support voltage gating of Ca(v)1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca(v)beta binds to the alpha-interaction domain (AID) and the IQ motif of the pore-forming alpha(1C) subunit, but these two interactions do not explain why the cardiac Ca(v)beta(2) subunit splice variants differentially modulate inactivation of Ca(2+) currents (I(Ca)). Previously we described beta(2Deltag), a functionally active splice variant of human Ca(v)beta(2) lacking MAGUK. By deletion analysis of beta(2Deltag), we have now identified a 41-amino acid C-terminal essential determinant (beta(2)CED) that stimulates I(Ca) in the absence of Ca(v)beta subunits and conveys a +20-mV shift in the peak of the I(Ca)-voltage relationship. The beta(2)CED is targeted by alpha(1C) to the plasma membrane, forms a complex with alpha(1C) but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the alpha(1C) subunit C terminus as a functionally relevant beta(2)CED binding site. The beta(2)CED interacts with LA/IQ in a Ca(2+)- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca(v)beta(2)/alpha(1C) interactions is sufficient to support I(Ca). However, beta(2)CED does not support Ca(2+)-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca(2+)-induced inactivation. The beta(2)CED is conserved only in Ca(v)beta(2) subunits. Thus, beta(2)CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca(v)beta(2)-subunit differential modulation of the Ca(v)1.2 calcium channel that in beta(2Deltag) occurs without MAGUK.</abstract><cop>United States</cop><pmid>18411278</pmid><doi>10.1074/jbc.M802035200</doi></addata></record> |
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| subjects | Amino Acid Motifs - physiology Amino Acid Sequence - genetics Binding Sites - physiology Calcium - metabolism Calcium Channels, L-Type - genetics Calcium Channels, L-Type - metabolism Calmodulin - genetics Calmodulin - metabolism Cell Line Cell Membrane - genetics Cell Membrane - metabolism Humans Ion Channel Gating - physiology Membrane Potentials - physiology Myocardium - metabolism Protein Structure, Tertiary - physiology Protein Subunits - genetics Protein Subunits - metabolism Sequence Deletion |
| title | New Determinant for the CaVbeta2 subunit modulation of the CaV1.2 calcium channel |
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