Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium
In cytosol-like medium (CLM) with a free [Ca2+] of 200 nm, a supramaximal concentration of inositol 1,4,5-trisphosphate (IP3) (30 μm) evoked 45Ca2+ release from type 3 IP3 receptors only after a latency of 48 ± 6 ms; this latency could not be reduced by increasing the IP3concentration. In CLM contai...
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description | In cytosol-like medium (CLM) with a free [Ca2+] of 200 nm, a supramaximal concentration of inositol 1,4,5-trisphosphate (IP3) (30 μm) evoked 45Ca2+ release from type 3 IP3 receptors only after a latency of 48 ± 6 ms; this latency could not be reduced by increasing the IP3concentration. In CLM containing a low free [Ca2+] (∼4 nm), 300 μm IP3 evoked45Ca2+ release after a latency of 66 ± 11 ms; this was reduced to 14 ± 3 ms when the [Ca2+] was 1 mm. Preincubation with CLM containing 100 μm Ca2+ caused a rapid (half-time = 33 ± 9 ms), complete, and fully reversible inhibition that could not be overcome by a high concentration of IP3 (300 μm). Hepatic (type 2) IP3 receptors were not inhibited by Ca2+ once they had bound IP3, but 100 μm Ca2+ rapidly inhibited type 3 IP3 receptors whether it was delivered before addition of IP3 or at any stage during a response to IP3. Ca2+ increases the affinity of IP3 for hepatic receptors by slowing IP3 dissociation, but Ca2+had no effect on IP3 binding to type 3 receptors. The rate of inhibition of type 3 IP3 receptors by Ca2+was faster than the rate of IP3 dissociation, and occurred at similar rates whether receptors had bound a high (adenophostin) or low affinity (3-deoxy-3-fluoro-IP3) agonist. Dissociation of agonist is not therefore required for Ca2+ to inhibit type 3 IP3 receptors. We conclude that type 2 and 3 IP3 receptors are each biphasically regulated by Ca2+, but by different mechanisms. For both, IP3 binding causes a stimulatory Ca2+-binding site to be exposed allowing Ca2+ to bind and open the channel. IP3 binding protects type 2 receptors from Ca2+ inhibition, but type 3 receptors are inhibited by Ca2+ whether or not they have IP3 bound. Increases in cytosolic [Ca2+] will immediately inhibit type 3 receptors, but inhibit type 2 receptors only after IP3 has dissociated. |
doi_str_mv | 10.1074/jbc.M200524200 |
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In CLM containing a low free [Ca2+] (∼4 nm), 300 μm IP3 evoked45Ca2+ release after a latency of 66 ± 11 ms; this was reduced to 14 ± 3 ms when the [Ca2+] was 1 mm. Preincubation with CLM containing 100 μm Ca2+ caused a rapid (half-time = 33 ± 9 ms), complete, and fully reversible inhibition that could not be overcome by a high concentration of IP3 (300 μm). Hepatic (type 2) IP3 receptors were not inhibited by Ca2+ once they had bound IP3, but 100 μm Ca2+ rapidly inhibited type 3 IP3 receptors whether it was delivered before addition of IP3 or at any stage during a response to IP3. Ca2+ increases the affinity of IP3 for hepatic receptors by slowing IP3 dissociation, but Ca2+had no effect on IP3 binding to type 3 receptors. The rate of inhibition of type 3 IP3 receptors by Ca2+was faster than the rate of IP3 dissociation, and occurred at similar rates whether receptors had bound a high (adenophostin) or low affinity (3-deoxy-3-fluoro-IP3) agonist. Dissociation of agonist is not therefore required for Ca2+ to inhibit type 3 IP3 receptors. We conclude that type 2 and 3 IP3 receptors are each biphasically regulated by Ca2+, but by different mechanisms. For both, IP3 binding causes a stimulatory Ca2+-binding site to be exposed allowing Ca2+ to bind and open the channel. IP3 binding protects type 2 receptors from Ca2+ inhibition, but type 3 receptors are inhibited by Ca2+ whether or not they have IP3 bound. Increases in cytosolic [Ca2+] will immediately inhibit type 3 receptors, but inhibit type 2 receptors only after IP3 has dissociated.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M200524200</identifier><identifier>PMID: 11875073</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Calcium - physiology ; Calcium Channels - physiology ; Cells, Cultured ; Cytosol - metabolism ; Inositol 1,4,5-Trisphosphate - analogs & derivatives ; Inositol 1,4,5-Trisphosphate - metabolism ; Inositol 1,4,5-Trisphosphate Receptors ; Kinetics ; Liver - metabolism ; Rats ; Receptors, Cytoplasmic and Nuclear - physiology ; Tumor Cells, Cultured</subject><ispartof>The Journal of biological chemistry, 2002-05, Vol.277 (20), p.17571-17579</ispartof><rights>2002 © 2002 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c440t-4e6d769511c574c3c43ae4d5d4e6aee3514fbdb31f3c5714132a7f4d09843dec3</citedby><cites>FETCH-LOGICAL-c440t-4e6d769511c574c3c43ae4d5d4e6aee3514fbdb31f3c5714132a7f4d09843dec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11875073$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Swatton, Jane E.</creatorcontrib><creatorcontrib>Taylor, Colin W.</creatorcontrib><title>Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>In cytosol-like medium (CLM) with a free [Ca2+] of 200 nm, a supramaximal concentration of inositol 1,4,5-trisphosphate (IP3) (30 μm) evoked 45Ca2+ release from type 3 IP3 receptors only after a latency of 48 ± 6 ms; this latency could not be reduced by increasing the IP3concentration. In CLM containing a low free [Ca2+] (∼4 nm), 300 μm IP3 evoked45Ca2+ release after a latency of 66 ± 11 ms; this was reduced to 14 ± 3 ms when the [Ca2+] was 1 mm. Preincubation with CLM containing 100 μm Ca2+ caused a rapid (half-time = 33 ± 9 ms), complete, and fully reversible inhibition that could not be overcome by a high concentration of IP3 (300 μm). Hepatic (type 2) IP3 receptors were not inhibited by Ca2+ once they had bound IP3, but 100 μm Ca2+ rapidly inhibited type 3 IP3 receptors whether it was delivered before addition of IP3 or at any stage during a response to IP3. Ca2+ increases the affinity of IP3 for hepatic receptors by slowing IP3 dissociation, but Ca2+had no effect on IP3 binding to type 3 receptors. The rate of inhibition of type 3 IP3 receptors by Ca2+was faster than the rate of IP3 dissociation, and occurred at similar rates whether receptors had bound a high (adenophostin) or low affinity (3-deoxy-3-fluoro-IP3) agonist. Dissociation of agonist is not therefore required for Ca2+ to inhibit type 3 IP3 receptors. We conclude that type 2 and 3 IP3 receptors are each biphasically regulated by Ca2+, but by different mechanisms. For both, IP3 binding causes a stimulatory Ca2+-binding site to be exposed allowing Ca2+ to bind and open the channel. IP3 binding protects type 2 receptors from Ca2+ inhibition, but type 3 receptors are inhibited by Ca2+ whether or not they have IP3 bound. Increases in cytosolic [Ca2+] will immediately inhibit type 3 receptors, but inhibit type 2 receptors only after IP3 has dissociated.</description><subject>Animals</subject><subject>Calcium - physiology</subject><subject>Calcium Channels - physiology</subject><subject>Cells, Cultured</subject><subject>Cytosol - metabolism</subject><subject>Inositol 1,4,5-Trisphosphate - analogs & derivatives</subject><subject>Inositol 1,4,5-Trisphosphate - metabolism</subject><subject>Inositol 1,4,5-Trisphosphate Receptors</subject><subject>Kinetics</subject><subject>Liver - metabolism</subject><subject>Rats</subject><subject>Receptors, Cytoplasmic and Nuclear - physiology</subject><subject>Tumor Cells, Cultured</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1rGzEQhkVpaZyk1x6DDqW3dfW11vqYmDoNpBSKA7kJrTSbVdi1NpK2xf--U2zIqVQw0mGeedE8hHzkbMmZVl-eW7f8LhirhcL7DVlw1shK1vzxLVkwJni1FnVzRs5zfmZ41Jq_J2ecN7pmWi7I49bmQm_C1NscHP0JT_NgS4h7Gju6O0xAJb3bxxxKHOguhTz1EcsWQNbBVGLKtD3QzaHEHAeM2NjBhXm8JO86O2T4cHovyMP2627zrbr_cXu3ub6vnFKsVApWXq_WNeeu1spJp6QF5WuPDQuAi6iu9a3knUSAKy6F1Z3ybN0o6cHJC_L5mDul-DJDLmYM2cEw2D3EORvNV5oJpf4L8qZeacUFgssj6FLMOUFnphRGmw6GM_NXukHp5lU6Dlydkud2BP-Knywj8OkI9OGp_x0SmDZE18NohNZGYKrG3RBrjhigr18BkskuwN6BxxFXjI_hX1_4A-d1m4U</recordid><startdate>20020517</startdate><enddate>20020517</enddate><creator>Swatton, Jane E.</creator><creator>Taylor, Colin W.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</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>7QP</scope><scope>7X8</scope></search><sort><creationdate>20020517</creationdate><title>Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium</title><author>Swatton, Jane E. ; Taylor, Colin W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c440t-4e6d769511c574c3c43ae4d5d4e6aee3514fbdb31f3c5714132a7f4d09843dec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Calcium - physiology</topic><topic>Calcium Channels - physiology</topic><topic>Cells, Cultured</topic><topic>Cytosol - metabolism</topic><topic>Inositol 1,4,5-Trisphosphate - analogs & derivatives</topic><topic>Inositol 1,4,5-Trisphosphate - metabolism</topic><topic>Inositol 1,4,5-Trisphosphate Receptors</topic><topic>Kinetics</topic><topic>Liver - metabolism</topic><topic>Rats</topic><topic>Receptors, Cytoplasmic and Nuclear - physiology</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Swatton, Jane E.</creatorcontrib><creatorcontrib>Taylor, Colin W.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Swatton, Jane E.</au><au>Taylor, Colin W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-05-17</date><risdate>2002</risdate><volume>277</volume><issue>20</issue><spage>17571</spage><epage>17579</epage><pages>17571-17579</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>In cytosol-like medium (CLM) with a free [Ca2+] of 200 nm, a supramaximal concentration of inositol 1,4,5-trisphosphate (IP3) (30 μm) evoked 45Ca2+ release from type 3 IP3 receptors only after a latency of 48 ± 6 ms; this latency could not be reduced by increasing the IP3concentration. In CLM containing a low free [Ca2+] (∼4 nm), 300 μm IP3 evoked45Ca2+ release after a latency of 66 ± 11 ms; this was reduced to 14 ± 3 ms when the [Ca2+] was 1 mm. Preincubation with CLM containing 100 μm Ca2+ caused a rapid (half-time = 33 ± 9 ms), complete, and fully reversible inhibition that could not be overcome by a high concentration of IP3 (300 μm). Hepatic (type 2) IP3 receptors were not inhibited by Ca2+ once they had bound IP3, but 100 μm Ca2+ rapidly inhibited type 3 IP3 receptors whether it was delivered before addition of IP3 or at any stage during a response to IP3. Ca2+ increases the affinity of IP3 for hepatic receptors by slowing IP3 dissociation, but Ca2+had no effect on IP3 binding to type 3 receptors. The rate of inhibition of type 3 IP3 receptors by Ca2+was faster than the rate of IP3 dissociation, and occurred at similar rates whether receptors had bound a high (adenophostin) or low affinity (3-deoxy-3-fluoro-IP3) agonist. Dissociation of agonist is not therefore required for Ca2+ to inhibit type 3 IP3 receptors. We conclude that type 2 and 3 IP3 receptors are each biphasically regulated by Ca2+, but by different mechanisms. For both, IP3 binding causes a stimulatory Ca2+-binding site to be exposed allowing Ca2+ to bind and open the channel. IP3 binding protects type 2 receptors from Ca2+ inhibition, but type 3 receptors are inhibited by Ca2+ whether or not they have IP3 bound. Increases in cytosolic [Ca2+] will immediately inhibit type 3 receptors, but inhibit type 2 receptors only after IP3 has dissociated.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11875073</pmid><doi>10.1074/jbc.M200524200</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Calcium - physiology Calcium Channels - physiology Cells, Cultured Cytosol - metabolism Inositol 1,4,5-Trisphosphate - analogs & derivatives Inositol 1,4,5-Trisphosphate - metabolism Inositol 1,4,5-Trisphosphate Receptors Kinetics Liver - metabolism Rats Receptors, Cytoplasmic and Nuclear - physiology Tumor Cells, Cultured |
title | Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium |
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