{"id":401,"date":"2018-01-10T13:44:52","date_gmt":"2018-01-10T12:44:52","guid":{"rendered":"http:\/\/confolab.sav.sk\/ovsb\/en\/?page_id=401"},"modified":"2024-02-16T13:49:47","modified_gmt":"2024-02-16T12:49:47","slug":"nih-firca-ro3-tw005543-1","status":"publish","type":"page","link":"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/completed-projects\/nih-firca-ro3-tw005543-1\/","title":{"rendered":"NIH FIRCA RO3 TW005543\/1"},"content":{"rendered":"<p><script type=\"text\/javascript\">\n<!--\nfunction launch(newURL, newName, newFeatures, orgName) {\n  var remote = open(newURL, newName, newFeatures);\n  if (remote.opener == null)\n    remote.opener = window;\n  remote.opener.name = orgName;\n  return remote;\n}\n\nfunction launchRemote(name) {\n  var address =  name;\n  myRemote = launch(address ,\n                    \"Okno\",\n                    \"height=500, width=850, left=50, top=50, alwaysLowered=0, alwaysRaised=0, channelmode=0, dependent=0, directories=0, fullscreen=0, hotkeys=1, location=0, menubar=0, resizable=0, scrollbars=0, status=0, titlebar=1, toolbar=0, z-lock=0\",\n                    \"myWindow\");\n}\n\/\/ -->>\n<\/script><\/p>\n<h2>Calcium signaling in cardiac excitation-contraction&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;<button onclick=\"goBack()\">Back<\/button> <\/h2>\n<p><script>\t \t \nfunction goBack() { window.history.go(-1); }\t \t \n<\/script><\/p>\n<table border=\"0\" width=\"100%\" cellspacing=\"1\" cellpadding=\"2\">\n<tbody>\n<tr>\n<td>\n<h3>Principal Investigator: Sandor Gyorke, Texas Tech University, Lubbock, TX, USA<br \/>\nInternational Collaborator: <a href=\"http:\/\/www.umfg.sav.sk\/ovsb\/en\/people\/researchers\/zahradnikova-a\/\">Alexandra Zahradn\u00edkov\u00e1<\/a>, <a href=\"http:\/\/www.umfg.sav.sk\/ovsb\/en\/people\/researchers\/zahradnik-i\/\">Ivan Zahradn\u00edk<\/a><\/h3>\n<h3>Duration: March 2001 &#8211; August 2004<br \/>\nCoordinating Organization: Texas Tech University, Lubbock, TX, USA<\/h3>\n<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Annotation:<\/span><\/h3>\n<p>Excitation-contraction coupling (ECC) in mammalian cardiac muscle relies on calcium signaling across the tubulo &#8211; reticular junction. It comprises a series of molecular events including: voltage-dependent activation of the plasmalemmal  L-type Ca2+ channels (DHPRs); diffusion and binding of injected Ca2+ ions within the tubulo-reticular gap; Ca2+-dependent activation of a juxtaposed cisternal ryanodine receptor calcium release channel (RyR); release of Ca2+ ions to the tubulo-reticular gap; amplification of the release by Ca2+-dependent activation of the adjacent RyR channels, and inhibition of the calcium current by Ca2+-dependent inactivation of the DHPR channels. All these events, stochastic in nature, are not sufficiently understood. Especially, it is not clear how they are orchestrated to provide efficient excitation-contraction coupling and gradation of the release with the stimulus. Our central hypothesis is that the specific microarchitecture of the tubulo-reticular junction, consisting of juxtaposed clusters of DHPR and RyR channels, together with their specific calcium-dependent gating properties, convey the unique properties of ECC in cardiac myocytes. We particularize this hypothesis in the concept of the excitation-contraction coupling unit (ECCU). The ECCU is understood as the whole set of channels in the cardiac dyadic junction, defined by their conductive and gating properties and by their topological disposition and ionic environment. The DHPR channels form an excitation unit &#8211; the subset of ECCU, which gives rise to calcium currents in response to voltage stimulus. The RyR channels form a release unit &#8211; the subset of the ECCU, which gives rise to elementary calcium transients (calcium sparks\/spikes).<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Keywords:<\/span><\/h3>\n<p>ryanodine receptor, cardiac myocyte, excitation-contraction coupling<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Objectives:<\/span><\/h3>\n<p>The objective of this proposal is to define the key steps in control of calcium release by excitation at the level of calcium signaling between individual channels forming the dyadic ECC unit and to determine their physiological significance. To achieve this objective, we will extensively employ the original model of calcium current kinetics with release dependent inactivation, and the new software for simulation of the electrophysiological experiment based on simulation of interacting channel clusters, both developed at the Slovak site. We will concentrate on three closely related specific aims. Specific Aim 1: To define the mechanisms of calcium signaling within the ECCU during activation of calcium release. The goal of these experiments is to derive the disposition of the ECCU and to determine which feed-forward calcium signaling steps within the ECCU are essential for the efficiency and reliability of calcium-induced calcium release (CICR).  Specific Aim 2: To determine the mechanism of DHPR inactivation by the released Ca2+ ions and to define its physiological significance. The goal of these experiments is to determine which feedback calcium signaling mechanisms within the ECCU are essential for the efficiency and stability of CICR. Specific Aim 3: To define the key steps controlling the gain and efficiency of the ECCU with implications on the gradation of E-C coupling at the whole-cell level. We hypothesize that the voltage- and time-dependence of the Ca2+ transient at the whole-cell level, and thus contraction, results from the summation of stochastically distributed responses of individual ECCUs to the stimulus.<\/td>\n<\/tr>\n<tr>\n<td>\n<h3><span class=\"H3\">Publications:<\/span><\/h3>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<table class=\"list\" border=\"0\" width=\"100%\" cellspacing=\"0\" cellpadding=\"4\">\n<tbody>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16260840?dopt=Citation\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1114\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/JGP-125x150.jpg\" alt=\"JGP\" width=\"75\" height=\"98\" \/><\/a><\/td>\n<td class=\"two\"><strong>Zahradnik I<\/strong>, Gyorke S, <strong>Zahradnikova A<\/strong> (2005). <a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/16260840?dopt=Citation\")'>Calcium activation of ryanodine receptor channels&#8211;reconciling RyR gating models with tetrameric channel structure.<\/a><i> J Gen Physiol.<\/i> 126: 515-527.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14522820\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1120\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/AJPCell-113x150.jpg\" alt=\"AJPCell\" width=\"75\" height=\"100\" \/><\/a><\/td>\n<td class=\"two\"><strong>Zahradnikova A<\/strong>, <strong>Kubalova Z<\/strong>, <strong>Pavelkova J<\/strong>, Gyorke S, <strong>Zahradnik I<\/strong> (2004). <a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14522820\")'>Activation of calcium release assessed by calcium release-induced inactivation of calcium current in rat cardiac myocytes.<\/a><i> Am J Physiol Cell Physiol.<\/i> 286: C330-41.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14535832?dopt=Citation\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1120\" src=\"http:\/\/www.biomed.cas.cz\/physiolres\/img\/S5_2015.jpg\" alt=\"AJPCell\" width=\"75\" height=\"100\" \/><\/a><\/td>\n<td class=\"two\"><strong>Dura M<\/strong>, <strong>Zahradnik I<\/strong>, <strong>Zahradnikova A<\/strong> (2003): <a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/14535832?dopt=Citation\")'>Kinetics of cardiac RyR channel gating studied at high temporal resolution.<\/a><i> Physiol Res.<\/i> 52: 571-578.<\/td>\n<\/tr>\n<tr>\n<td class=\"small\"><a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12839831?dopt=Citation\")'><img decoding=\"async\" loading=\"lazy\" class=\"alignnone wp-image-1120\" src=\"http:\/\/confolab.sav.sk\/ovsb\/wp-content\/uploads\/AJPCell-113x150.jpg\" alt=\"AJPCell\" width=\"75\" height=\"100\" \/><\/a><\/td>\n<td class=\"two\"><strong>Zahradnikova A<\/strong>, <strong>Dura M<\/strong>, Gyorke I, Escobar AL, <strong>Zahradnik I<\/strong>, Gyorke S (2003). <a href='javascript:launchRemote(\"http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/12839831?dopt=Citation\")'>Regulation of dynamic behavior of cardiac ryanodine receptor by Mg2+ under simulated physiological conditions.<\/a><i> Am J Physiol Cell Physiol.<\/i> 285: C1059-1070.<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n","protected":false},"excerpt":{"rendered":"<p>Calcium signaling in cardiac excitation-contraction&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Back Principal Investigator: Sandor Gyorke, Texas Tech University, Lubbock, TX, USA International Collaborator: Alexandra Zahradn\u00edkov\u00e1, Ivan Zahradn\u00edk Duration: March 2001 &#8211;&#8230;<span class=\"excerpt_more\"><a href=\"https:\/\/confolab.sav.sk\/ovsb\/en\/projects\/completed-projects\/nih-firca-ro3-tw005543-1\/\">\u010d\u00edta\u0165 \u010falej &raquo;<\/a><\/span><\/p>\n","protected":false},"author":1,"featured_media":0,"parent":199,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/401"}],"collection":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/comments?post=401"}],"version-history":[{"count":3,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/401\/revisions"}],"predecessor-version":[{"id":1623,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/401\/revisions\/1623"}],"up":[{"embeddable":true,"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/pages\/199"}],"wp:attachment":[{"href":"https:\/\/confolab.sav.sk\/ovsb\/en\/wp-json\/wp\/v2\/media?parent=401"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}