The Calcium-Calmodulin System
Enrique Pimentel in Handbook of Growth Factors, 2017
The calpains are neutral proteases that have an absolute Ca2+ dependence for activity.226 They have been isolated from the cytosolic fraction of animal tissues or cells, but may be translocated to the cell membrane under certain conditions. The two calpains, calpain I and calpain II, have an indentical 30-kDa regulatory subunit but two distinct 80-kDa catalytic subunits. Both types of calpain subunits contain calmodulin-like Ca2+-binding domains at their carboxy-terminal ends, and these domains confer Ca2+ sensitivity to the calpains. The activity of calpains is also regulated by an endogenous calpain inhibitor protein, termed calpastatin. The biological functions of calpains are little understood; however, it is clear that they do not have general proteolytic activity, but rather catalyze specific and limited cleavage of specific substrates. Calpain I and calpain II appear to have identical substrate specificities. Endogenous substrates for calpains include enzymes such as kinases as well as myofibrilar, membrane, cytoskeletal, and receptor proteins. More than half of calmodulin-binding proteins are calpain substrates in vitro.226 These proteins are recognized by calpains through the presence of specific amino acid sequences in them, called PEST sequences, which contain proline (P), glutamic acid (E), serine (S), and threonine (T). The Jun and Fos oncoproteins, which contain PEST sequences and form heterodimers with binding activity for AP-1 DNA sites, are substrates for calpain.227 Some small proteins not containing PEST sequences may also be calpain substrates.
Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
In attempts to identify other proteins involved in the development of MDR, several workers have screened cells for the overexpression of proteins other than P-glycoprotein. Meyers and co-workers201,202 have reported the overexpression of a 22-kDa protein (termed V19 or sorcin) in MDR Chinese hamster and mouse cells selected for resistance to vincristine. A protein of similar size has been shown to be overexpressed in a number of other multidrug-resistant cell lines.203,204 This protein has been purified and sequenced and has been shown to have amino acid sequence homology with the calcium-binding light chain of calpain.205
Glycine Cytoprotection and Inhibition of Nonlysosomal Calcium-Dependent Proteolysis During Anoxic Injury of Rat Hepatocytes
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
Our numerous observations suggest an association between amino acid cytoprotection and inhibition of calpain protease activity during anoxic hepatocellular injury. First, the amino acid profile for cytoprotection and inhibition of calpain protease activity is identical. Second, the concentrations of glycine and alanine providing maximal inhibition of calpain protease activity are identical to those concentrations providing maximal cytoprotection. Third, the stimulation of calpain protease activity does not appear to be a post-necrotic event; calpain-like protease activity was measured at 30 min when anoxic cell death is minimal.
Effects of 6-(Methylsulfinyl)hexyl Isothiocyanate Ingestion on Muscle Damage after Eccentric Exercise in Healthy Males: A Pilot Placebo-Controlled Double-Blind Crossover Study
Published in Journal of Dietary Supplements, 2022
Yoko Tanabe, Nobuhiko Akazawa, Mio Nishimaki, Kazuhiro Shimizu, Naoto Fujii, Hideyuki Takahashi
Many factors can contribute to the muscle damage-associated loss of muscle force, including abnormalities in excitation-contraction coupling (8), disruption in muscle fibers to force-generating structures such as actin and myosin (9), and altered central nervous system (10,11). In addition to these factors, recent animal studies suggest that a primarily calpain-associated proteolysis of key muscle contraction-associated proteins could, at least in part, lead to such a large and long-lasting, eccentric contraction-associated force deficit (12,13). A mechanical force, especially induced by eccentric contraction, leads to overstretching and disruption of sarcomeres. This response is followed by increased Ca2+ influx into the muscle cells due to mechanical disruption in the membrane (14) and opening stretch-activated Ca2+ channels (15). Ca2+ in the muscle cells then binds to the domain of calpain in a Ca2+-dependent manner, cleaving a variety of protein substrates including cytoskeletal and myofibrillar proteins such as α-actinin and titin, ultimately accelerating myofibrillar structure degradation (16,17). In addition, calpain activity inhibition promotes the restoration process of force production after eccentric contractions in mice (12) Therefore, if post-exercise calpain activity is suppressed, muscle damage and associated responses (e.g. elevated CK, U-titin, and T2) might be partially prevented.
The Sustained Release of Tafluprost with a Drug Delivery System Prevents the Axonal Injury-induced Loss of Retinal Ganglion Cells in Rats
Published in Current Eye Research, 2020
Kota Sato, Yurika Nakagawa, Kazuko Omodaka, Hiroyuki Asada, Shinobu Fujii, Kenji Masaki, Toru Nakazawa
We demonstrated the effect of the tafluprost DDS on calpain in rat retinas. Calpain, a member of the cysteine protease family, has been implicated in the regulation of cytoskeletal/plasma membrane attachments, cell motility, differentiation, proliferation, apoptosis, signal transduction and gene expression.35 Calpain, which has been reported to be associated with various neurodegenerative diseases, is activated by increased intracellular levels of calcium.35,46,47 In the retina, calpain is present in the ganglion cells and the nerve fibers, and its activation occurs during retinal damage caused by high IOP, axotomy, or excitotoxic injury.32,47–52 Excessive calcium influx into cells is considered to be an important causative factor for RGC apoptosis. Previous research has shown that the risk of vision loss in NTG patients increases significantly when calcium channel blockers are not used,53 and that tafluprost decreases the intracellular calcium concentration in vitro.23 Thus, our tafluprost DDS might contribute to the suppression of excessive calpain activation, probably via decreasing calcium influx into the cells, suggesting that tafluprost has a neuroprotective effect against RGC damage caused by axonal injury.
Modulators of calpain activity: inhibitors and activators as potential drugs
Published in Expert Opinion on Drug Discovery, 2020
Levente Endre Dókus, Mo’ath Yousef, Zoltán Bánóczi
Calpains are expressed in different organisms including in humans, other invertebrates, yeast, other fungi and bacteria. These intracellular enzymes cleave their substrate proteins in a well-determined manner. This limited proteolysis activates or deactivates the substrate proteins; thus calpains have either a regulatory or signaling function rather than in protein digestion in cells as is the case with proteasomal or lysosomal enzymes. Because of this, their activity should be under strong control in cells. Two proteins of calpain regulation are well-studied and play vital roles. One is the small regulatory subunit (calpain 4) that is necessary to stabilize the structure of at least calpain 1 and 2 [14]. The other protein is the calpastatin that has an inhibitory effect on dimeric calpains (e.g. calpain 1 and 2) [15]. Beside them, the Ca2+ ion concentration is the main factor. At increased Ca2+ ion concentration, these enzymes are activated, although this happens only at high concentrations (3–50 μM and 0.4–0.8 mM for calpain 1 and 2, respectively) in vitro. This is highly above the intracellular Ca2+ ion concentration (<0.05 μM). Thus, other mechanisms should be involved in the activation of calpains (e.g. the relocalization into the mitochondria or nucleus; membrane binding, phosphorylation) [16].
Related Knowledge Centers
- Calcium
- Calpastatin
- Cysteine Protease
- Protease
- Tissue
- Brain
- Skeletal Muscle
- Papain-Like Protease
- Calpain Small Subunit 1
- Lens