CaMPDB: A RESOURCE FOR CALPAIN AND MODULATORY PROTEOLYSIS

duVerle, David A.; Takigawa, Ichigaku; Ono, Yasuko; Sorimachi, Hiroyuki; Mamitsuka, Hiroshi

doi:10.1142/9781848165786_0017

Cited by 41 publications

(57 citation statements)

References 17 publications

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“…Alternatively, mutagenesis at this position may not fully disrupt the tertiary structure recognized by the protease; such observations are not uncommon (28). There is significant overlap in calpain substrates between family members, so it is possible that other calpains may activate TRPC5 as well (26). The data in Fig.…”

Section: Discussionmentioning

confidence: 91%

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Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse

Kaczmarek

Riccio

Clapham

2012

Proc. Natl. Acad. Sci. U.S.A.

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The nonselective cation channel transient receptor potential canonical (TRPC)5 is found predominantly in the brain and has been proposed to regulate neuronal processes and growth cones. Here, we demonstrate that semaphorin 3A-mediated growth cone collapse is reduced in hippocampal neurons from TRPC5 null mice. This reduction is reproduced by inhibition of the calcium-sensitive protease calpain in wild-type neurons but not in TRPC5 −/− neurons. We show that calpain-1 and calpain-2 cleave and functionally activate TRPC5. Mutation of a critical threonine at position 857 inhibits calpain-2 cleavage of the channel. Finally, we show that the truncated TRPC5 predicted to result from calpain cleavage is functionally active. These results indicate that semaphorin 3A initiates growth cone collapse via activation of calpain that in turn potentiates TRPC5 activity. Thus, TRPC5 acts downstream of semaphorin signaling to cause changes in neuronal growth cone morphology and nervous system development.A multitude of signals regulate development of the nascent mammalian nervous system. Secreted and contact-mediated extracellular cues may be transduced to the interior of the cell by surface receptors, initiating both short and long-term changes in cellular physiology. Proper formation of the nervous system requires axons, dendrites, and even the soma of neurons to accurately traverse great distances and connect with specific targets. Such movements require spatially and temporally regulated expression of extracellular guidance cue molecules by the surrounding tissues or distant targets that bind to surface receptors and attract or repel the developing neuron (1, 2).Several members of the semaphorin class of secreted guidance peptides cause intracellular calcium elevations upon binding to their cognate receptors (3, 4), but how they effect this change is unclear. Transient receptor potential (TRP) proteins, a family of calcium-permeable nonselective cation channels, are widespread in the nervous system and affect neuronal development and nervous system function (5). In particular, studies of TRP canonical (TRPC)5 suggest that it influences the growth of neuronal processes (axons or dendrites). TRPC5 mRNA is found at high levels in several brain regions, including the hippocampus, olfactory bulb, amygdala, and cerebellum, and may also be detected diffusely throughout the cortex (6, 7). siRNA-mediated knockdown or pharmacologic inhibition of this channel has been reported to both stimulate and inhibit neurite sprouting and extension, depending upon the cell type and assays used (8-10). In addition, the TRPC5 null mouse displays deficits in dendritic development in the cerebellum (11) and abnormal amygdalar function (12). Little is known about normal modes of TRPC5 activation, although G protein-coupled receptor (GPCR-Gαq) signaling (13) and other molecules (14-19) strongly potentiate TRPC5 current.Semaphorin (sema)3A is a secreted guidance peptide that binds to the neuropilin-1/plexin A1 receptor complex and may cause either attract...

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Section: Discussionmentioning

confidence: 91%

“…edu. (26). The ubiquitous proteases calpain-1 (μ-calpain) and calpain-2 (m-calpain) have the highest expression levels in brain.…”

Section: Trpc5 and Calpain Are Critical To Sema3a-induced Growth Conementioning

confidence: 99%

Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse

Kaczmarek

Riccio

Clapham

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally some calpains are ubiquitous (1, 2, 5, 7, 10, 13, and 15), whereas others are more tissue-restricted in expression [3a (striated muscle), 6 (placenta), 8 (stomach), 9 (digestive tract), 11 (testis), and 12 (hair follicle cells)] 104 .…”

Section: Calpainsmentioning

confidence: 99%

“…In some cases binding to membranes or other proteins may stabilize the calpains, limit autolysis and help direct activity to specific substrates, but other evidence suggests membrane binding and specifically exposure to membrane phospholipids reduces the Ca2+ activation threshold 103 . In addition, activity of dimeric calpains (CAPN1, 2 and 9) is also specifically inhibited by calpastatin 104 , a monomeric protein that has recently been shown to bind calpain in the presence of Ca2+ and assumes a structure which allows inhibition of the calpain active site while avoiding proteolytic cleavage itself [106][107] .…”

Section: Calpainsmentioning

confidence: 99%

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

Wing

Lecker

Jagoe

2011

Critical Reviews in Clinical Laboratory Sciences

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Improvements in health in the past decades have resulted in increased numbers of the elderly in both developed and developing regions of the world. Advances in therapy have also increased the prevalence of patients with chronic and degenerative diseases. Muscle wasting, a feature of most chronic diseases, is prominent in the elderly and contributes to both morbidity and mortality. A major research goal has been to identify the proteolytic system(s) that is responsible for the degradation of proteins that occurs in muscle atrophy. Findings over the past 20 years have clearly confirmed an important role of the ubiquitin proteasome system in mediating muscle proteolysis, particularly that of myofibrillar proteins. However, recent observations have provided evidence that autophagy, calpains and caspases also contribute to the turnover of muscle proteins in catabolic states, and furthermore, that these diverse proteolytic systems interact with each other at various levels. Importantly, a number of intracellular signaling pathways such as the IGF1/AKT, myostatin/Smad, PGC1, cytokine/NFκB, and AMPK pathways are now known to interact and can regulate some of these proteolytic systems in a coordinated manner. A number of loss of function studies have identified promising therapeutic approaches to the prevention and treatment of wasting. However, additional biomarkers and other approaches to improve early identification of patients who would benefit from such treatment need to be developed. The current data suggests a network of interacting proteolytic and signaling pathways in muscle. Future studies are needed to improve understanding of the nature and control of these interactions and how they work to preserve muscle function under various states of growth and atrophy.

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“…Although casein is not an in vivo substrate of calpain, it is a very good in vitro substrate and is used to assay calpain activity. The complete rules governing substrate specifi city remain unclear; however, some preferences for cleavage site sequences have been reported [35,165] (see also http://calpain.org). Calpain is also thought to recognize a wide range of 3d substrate structures.…”

Section: Structure and Function Of Conventional Calpainsmentioning

confidence: 99%

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

2010

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Abstract:Calpains are intracellular Ca 2+ -dependent cysteine proteases (Clan CA, family C02, EC 3.4.22.17) found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolysing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". The human genome has 15 genes that encode a calpain-like protease domain, generating diverse calpain homologues that possess combinations of several functional domains such as Ca 2+ -binding domains and Zn-finger domains. The importance of the physiological roles of calpains is reflected in the fact that particular defects in calpain functionality cause a variety of deficiencies in many different organisms, including lethality, muscular dystrophies, lissencephaly, and tumorigenesis. In this review, the unique characteristics of this distinctive protease superfamily are introduced in terms of genetically modified animals, some of which are animal models of calpain deficiency diseases.

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CaMPDB: A RESOURCE FOR CALPAIN AND MODULATORY PROTEOLYSIS

Cited by 41 publications

References 17 publications

Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse

Calpain cleaves and activates the TRPC5 channel to participate in semaphorin 3A-induced neuronal growth cone collapse

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

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