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Here, we provide a comprehensive analysis of the structure\u2013function relationships of the eight calcins known to date, based on their primary sequence, three-dimensional modeling, and functional effects on skeletal RyRs (RyR1). Primary sequence alignment and evolutionary analysis show high similarity among all calcins (\u226578.8% identity). Other common characteristics include an inhibitor cysteine knot (ICK) motif stabilized by three pairs of disulfide bridges and a dipole moment (DM) formed by positively charged residues clustering on one side of the molecule and neutral and negatively charged residues segregating on the opposite side. [3H]Ryanodine binding assays, used as an index of the open probability of RyRs, reveal that all eight calcins activate RyR1 dose-dependently with Kd values spanning approximately three orders of magnitude and in the following rank order: opicalcin1 &amp;gt; opicalcin2 &amp;gt; vejocalcin &amp;gt; hemicalcin &amp;gt; imperacalcin &amp;gt; hadrucalcin &amp;gt; maurocalcin &amp;gt;&amp;gt; urocalcin. All calcins significantly augment the bell-shaped [Ca2+]-[3H]ryanodine binding curve with variable effects on the affinity constants for Ca2+ activation and inactivation. In single channel recordings, calcins induce the appearance of a subconductance state in RyR1 that has a unique fractional value (\u223c20% to \u223c60% of the full conductance state) but bears no relationship to binding affinity, DM, or capacity to stimulate Ca2+ release. Except for urocalcin, all calcins at 100 nM concentration stimulate Ca2+ release and deplete Ca2+ load from skeletal sarcoplasmic reticulum. The natural variation within the calcin family of peptides offers a diversified set of high-affinity ligands with the capacity to modulate RyRs with high dynamic range and potency.<\/jats:p>","DOI":"10.1085\/jgp.201511499","type":"journal-article","created":{"date-parts":[[2016,4,25]],"date-time":"2016-04-25T09:19:31Z","timestamp":1461575971000},"page":"375-394","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["Structure\u2013function relationships of peptides forming the calcin family of ryanodine receptor ligands"],"prefix":"10.1085","volume":"147","author":[{"given":"Liang","family":"Xiao","sequence":"first","affiliation":[{"name":"Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China 1"},{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina B.","family":"Gurrola","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Morelos 62271, M\u00e9xico 2"},{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen R.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"SanMartin","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando Z.","family":"Zamudio","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Morelos 62271, M\u00e9xico 2"},{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Marine Biotechnology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lourival D.","family":"Possani","sequence":"additional","affiliation":[{"name":"Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnolog\u00eda, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Cuernavaca, Morelos 62271, M\u00e9xico 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research, Cardiovascular Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2016,4,25]]},"reference":[{"key":"2023072623475823100_bib1","doi-asserted-by":"crossref","first-page":"18750","DOI":"10.1016\/S0021-9258(18)37347-2","article-title":"Mechanism of anthraquinone-induced calcium release from skeletal muscle sarcoplasmic reticulum","volume":"263","author":"Abramson","year":"1988","journal-title":"J. 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