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calpain activity was first identified four decades ago, a clear understanding of the substrates and functions of the enzymes has remained elusive. In large part, this has been due to the lack of inhibitors capable of specifically down-regulating the calpains without affecting other proteases. In the past decade, the story has been further complicated by the discovery of a number of previously unknown isoforms which may be differently regulated and have different substrate specificity. Gene targeting in mice has provided a powerful approach to examine the physiologic roles of individual calpain isoforms. This was first used to disrupt the Capn4 gene, encoding the small regulatory subunit common to both μ- and m-calpain. Two independent laboratories observed embryonic lethality in Capn4 knockout mice, albeit at different stages of development [31,32]. These observations supported the hypothesis that the small subunit is required for both μ- and m-calpain, and furthermore suggested four possibilities regarding their requirement for embryonic development: 1) both isoforms were required; 2) μ-calpain was required; 3) m-calpain was required, or 4) μ- and m-calpain are redundant, and one or the other isoform was required. These options were narrowed down by the subsequent observation that Capn1-/- mice, which lack the μ-calpain catalytic subunit, were healthy and fertile, although platelet aggregation and clot retraction defects were observed [33]. At that point, we were left with the last two possibilities that either m-calpain was specifically required during embryogenesis, or that either isoform alone was sufficient for sustaining embryonic viability."}

{"project":"craft-ca-core-dev","denotations":[{"id":"T12223","span":{"begin":1664,"end":1673},"obj":"UBERON:0000922"},{"id":"T12222","span":{"begin":1620,"end":1627},"obj":"SO:0001060"},{"id":"T12221","span":{"begin":1590,"end":1603},"obj":"GO:0009790"},{"id":"T12220","span":{"begin":1406,"end":1426},"obj":"GO:0070527"},{"id":"T12219","span":{"begin":1406,"end":1414},"obj":"CL:0000233"},{"id":"T12218","span":{"begin":1342,"end":1369},"obj":"PR:000005009"},{"id":"T12217","span":{"begin":1321,"end":1325},"obj":"NCBITaxon:10088"},{"id":"T12216","span":{"begin":1312,"end":1317},"obj":"PR:000005009"},{"id":"T12215","span":{"begin":1222,"end":1229},"obj":"SO:0001060"},{"id":"T12214","span":{"begin":1085,"end":1093},"obj":"SO:0001060"},{"id":"T12213","span":{"begin":1054,"end":1075},"obj":"GO:0009790"},{"id":"T12212","span":{"begin":1054,"end":1063},"obj":"UBERON:0000922"},{"id":"T12211","span":{"begin":814,"end":818},"obj":"NCBITaxon:10088"},{"id":"T12210","span":{"begin":799,"end":804},"obj":"PR:000005022"},{"id":"T12209","span":{"begin":776,"end":785},"obj":"UBERON:0000922"},{"id":"T12208","span":{"begin":686,"end":696},"obj":"GO:0065007"},{"id":"T12207","span":{"begin":661,"end":665},"obj":"SO:0000704"},{"id":"T12206","span":{"begin":655,"end":660},"obj":"PR:000005022"},{"id":"T12205","span":{"begin":610,"end":618},"obj":"SO:0001060"},{"id":"T12204","span":{"begin":517,"end":521},"obj":"NCBITaxon:10088"},{"id":"T12203","span":{"begin":499,"end":503},"obj":"SO:0000704"},{"id":"T12202","span":{"begin":447,"end":456},"obj":"GO:0065007"},{"id":"T12201","span":{"begin":413,"end":421},"obj":"SO:0001060"},{"id":"T12200","span":{"begin":204,"end":214},"obj":"CHEBI:35222"}],"text":"Although calpain activity was first identified four decades ago, a clear understanding of the substrates and functions of the enzymes has remained elusive. In large part, this has been due to the lack of inhibitors capable of specifically down-regulating the calpains without affecting other proteases. In the past decade, the story has been further complicated by the discovery of a number of previously unknown isoforms which may be differently regulated and have different substrate specificity. Gene targeting in mice has provided a powerful approach to examine the physiologic roles of individual calpain isoforms. This was first used to disrupt the Capn4 gene, encoding the small regulatory subunit common to both μ- and m-calpain. Two independent laboratories observed embryonic lethality in Capn4 knockout mice, albeit at different stages of development [31,32]. These observations supported the hypothesis that the small subunit is required for both μ- and m-calpain, and furthermore suggested four possibilities regarding their requirement for embryonic development: 1) both isoforms were required; 2) μ-calpain was required; 3) m-calpain was required, or 4) μ- and m-calpain are redundant, and one or the other isoform was required. These options were narrowed down by the subsequent observation that Capn1-/- mice, which lack the μ-calpain catalytic subunit, were healthy and fertile, although platelet aggregation and clot retraction defects were observed [33]. At that point, we were left with the last two possibilities that either m-calpain was specifically required during embryogenesis, or that either isoform alone was sufficient for sustaining embryonic viability."}

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In large part, this has been due to the lack of inhibitors capable of specifically down-regulating the calpains without affecting other proteases. In the past decade, the story has been further complicated by the discovery of a number of previously unknown isoforms which may be differently regulated and have different substrate specificity. Gene targeting in mice has provided a powerful approach to examine the physiologic roles of individual calpain isoforms. This was first used to disrupt the Capn4 gene, encoding the small regulatory subunit common to both μ- and m-calpain. Two independent laboratories observed embryonic lethality in Capn4 knockout mice, albeit at different stages of development [31,32]. These observations supported the hypothesis that the small subunit is required for both μ- and m-calpain, and furthermore suggested four possibilities regarding their requirement for embryonic development: 1) both isoforms were required; 2) μ-calpain was required; 3) m-calpain was required, or 4) μ- and m-calpain are redundant, and one or the other isoform was required. These options were narrowed down by the subsequent observation that Capn1-/- mice, which lack the μ-calpain catalytic subunit, were healthy and fertile, although platelet aggregation and clot retraction defects were observed [33]. At that point, we were left with the last two possibilities that either m-calpain was specifically required during embryogenesis, or that either isoform alone was sufficient for sustaining embryonic viability."}