Modulation of rat brain calpastatin efficiency by post‐translational modifications

Salamino, Franca; Averna, Monica; Tedesco, Ilaria; Tullio, Roberta De; Melloni, Edon; Pontremoli, S.

doi:10.1016/s0014-5793(97)00819-3

Cited by 55 publications

(74 citation statements)

References 37 publications

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“…It has been also demonstrated previously that both in vivo and in vitro -calpain seems to be involved in the inhibitor fragmentation, generating free active inhibitory domains, whereas m-calpain digests calpastatin producing inactive peptides (13)(14)(15). The different kinds of degradation accomplished by the two calpains is consistent with the hypothesis that fragmentation of calpastatin by -calpain, the first step of the inhibitor digestion process, corresponds to a local increase in active calpastatin species.…”

supporting

confidence: 86%

“…ural inhibitor protein calpastatin (13,42,43). An alternative exon splicing at the level of L-domain seems necessary to produce tissue-specific calpastatin molecules (44).…”

Section: Discussionmentioning

confidence: 99%

“…At the end of the electrophoretic run, the gel was washed with buffer A containing 20% methanol to remove any remaining SDS. After 20 min, the gel was transferred to buffer A without methanol and stirred gently for additional 20 min; then the gel lanes containing calpastatin were cut in 0.3-cm slices (13). Proteins were extracted from each slice by incubation in buffer A (0.3 ml) for 5 h. The treatment was repeated three times, and the solutions obtained from each sample (0.9 ml total) were pooled.…”

Section: Methodsmentioning

confidence: 99%

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Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

Averna¹,

Tullio²,

Salamino³

et al. 2001

Journal of Biological Chemistry

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Hypertensive rats from the Milan strain show a significant decrease in calpastatin activity as compared with normotensive control animals. Calpastatin deficiency is age-related and highly relevant in kidney, heart, and erythrocytes and of minor entity in brain tissue. In normotensives the changes during aging in the levels of calpastatin activity and mRNA are consistent with an increase of calpastatin protein. In hypertensive rats such a relationship during aging is not observed, because a progressive accumulation of mRNA is accompanied by a lower amount of calpastatin protein as compared with control rats. Together with the low level of calpastatin in kidney of hypertensive rats, a progressive accumulation of an active 15-kDa calpastatin fragment, previously shown to represent a typical product of calpain-mediated calpastatin degradation, is also observed. Evidence for such intracellular proteolysis by Ca 2؉ -activated calpain is provided by the normalization of the calpastatin level, up to that of control animals, in hypertensive rats treated with drugs known to reduce both blood pressure and intracellular Ca 2؉ influx. Further evidence is provided by the disappearance, in these conditions, of the 15-kDa calpastatin fragment. These data allow the conclusion that calpastatin degradation is a relevant part of the overall mechanism for regulating calpain activity.

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supporting

confidence: 86%

“…ural inhibitor protein calpastatin (13,42,43). An alternative exon splicing at the level of L-domain seems necessary to produce tissue-specific calpastatin molecules (44).…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

Averna¹,

Tullio²,

Salamino³

et al. 2001

Journal of Biological Chemistry

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“…Adachi et al (1991) showed that phosphorylation increased the proportion of CAST bound to membranes and Salamino et al (1997) demonstrated that phosphorylation decreased CAST inhibitory efficiency. Calpastatin phosphorylation could therefore influence proteolysis and ultimately have an effect on tenderness and other related meat quality traits.…”

Section: Discussionmentioning

confidence: 99%

New alleles in calpastatin gene are associated with meat quality traits in pigs1

Ciobanu

Bastiaansen²,

Lonergan

et al. 2004

Journal of Animal Science

146

110

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Suggestive QTL affecting raw firmness scores and average Instron force, tenderness, juiciness, and chewiness on cooked meat were mapped to pig chromosome 2 using a three-generation intercross between Berkshire and Yorkshire pigs. Based on its function and location, the calpastatin (CAST) gene was considered to be a good candidate for the observed effects. Several missense and silent mutations were identified in CASTand haplotypes covering most of the coding region were constructed and used for association analyses with meat quality traits. Results demonstrated that one CAST haplotype was significantly associated with lower Instron force and cooking loss and higher juiciness and, therefore, this haplotype is associated with higher eating quality. Some of the sequence variation identified may be associated with differences in phosphorylation of CAST by adenosine cyclic 3′, 5′-monophosphate-dependent protein kinase and may in turn explain the meat quality phenotypic differences. The beneficial haplotype was present in all the commercial breeds tested and may provide significant improvements for the pig industry and consumers because it can be used in markerassisted selection to produce naturally tender and juicy pork without additional processing steps. ABSTRACT: Suggestive QTL affecting raw firmness scores and average Instron force, tenderness, juiciness, and chewiness on cooked meat were mapped to pig chromosome 2 using a three-generation intercross between Berkshire and Yorkshire pigs. Based on its function and location, the calpastatin (CAST) gene was considered to be a good candidate for the observed effects. Several missense and silent mutations were identified in CAST and haplotypes covering most of the coding region were constructed and used for association analyses with meat quality traits. Results demonstrated that one CAST haplotype was significantly associated with

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“…It is not known whether the 2% of membrane-bound calpastatin in bovine cardiac muscle (279) was phosphorylated, but membrane-bound calpastatin can inhibit the calpains as effectively as cytosolic calpastatin (280); hence, the physiological significance of membrane-associated calpastatin is unclear. In vitro phosphorylation of rat brain calpastatin by either PKA or PKC (382) or by PKC (13) has been reported to decrease its efficiency (increase the concentration required for half-maximal inhibition) in inhibiting either -or m-calpain. The PKA phosphorylation occurred in the NH 2 -terminal part of calpastatin, and the PKC phosphorylation occurred on Ser-13 of rat calpastatin (rat calpastatin lacks the XL domain, so numbering starts with Met-1 of the L-domain; Ref.…”

Section: B Properties Of Calpastatinmentioning

confidence: 99%

The Calpain System

Goll

Thompson

et al. 2003

Physiological Reviews

2,568

2,801

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Goll, Darrel E., Valery F. Thompson, Hongqi Li, Wei Wei, and Jinyang Cong. The Calpain System. Physiol Rev 83: 731–801, 2003; 10.1152/physrev.00029.2002.—The calpain system originally comprised three molecules: two Ca2+-dependent proteases, μ-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both μ- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55–65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six “domains” in the 80-kDa subunit: 1) a 19-amino acid NH2-terminal sequence; 2) and 3) two domains that constitute the active site, IIa and IIb; 4) domain III; 5) an 18-amino acid extended sequence linking domain III to domain IV; and 6) domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of μ- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.

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Modulation of rat brain calpastatin efficiency by post‐translational modifications

Cited by 55 publications

References 37 publications

Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

Age-dependent Degradation of Calpastatin in Kidney of Hypertensive Rats

New alleles in calpastatin gene are associated with meat quality traits in pigs1

The Calpain System

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