Calpain
Encyclopedia
A calpain (ˈkælpeɪn; ) is a protein belonging to the family of calcium
-dependent, non-lysosomal
cysteine
protease
s (proteolytic enzyme
s) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS
database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1
, and the endogenous calpain-specific inhibitor, calpastatin
.
, lens of the eye and other tissue
s. In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle
. These activities were caused by an intracellular cysteine protease not associated with the lysosome
and having an optimum activity at neutral pH
, which clearly distinguished it from the cathepsin
family of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis
on its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known, it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signalling protein, calmodulin
, and the cysteine protease of papaya
, papain
. Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed μ("mu")-calpain and m-calpain (a.k.a. calpain I and II), that differed primarily in their calcium requirements in vitro. Their names reflect the fact that they are activated by micro- and nearly millimolar concentrations of Ca2+ within the cell, respectively.
To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric
isoforms share an identical small (28k) subunit (CAPNS1
(formerly CAPN4)), but have distinct large (80k) subunits, known as calpain 1 and calpain 2 (each encoded by the CAPN1
and CAPN2
genes respectively).
sequence is uniquely recognized by calpains. Amongst protein substrates, tertiary structure
elements rather than primary amino acid sequences
are likely responsible for directing cleavage to a specific substrate. Amongst peptide
and small-molecule substrates, the most consistently reported specificity is for small, hydrophobic amino acids (e.g. leucine
, valine
and isoleucine
) at the P2 position, and large hydrophobic amino acids (e.g. phenylalanine
and tyrosine
) at the P1 position. Arguably, the best currently available fluorogenic calpain substrate is (EDANS
)-Glu-Pro-Leu-Phe=Ala-Glu-Arg-Lys-(DABCYL), with cleavage occurring at the Phe=Ala bond.
database.
and cell cycle
progression, as well as cell-type specific functions such as long-term potentiation
in neuron
s and cell fusion
in myoblast
s. Under these physiological conditions, a transient and localized influx of calcium into the cell activates a small local population of calpains (for example, those close to Ca2+ channels), which then advance the signal transduction pathway by catalyzing the controlled proteolysis of its target proteins. Other reported roles of calpains are in cell
function, helping to regulate clotting and the diameter of blood vessel
s, and playing a role in memory
. Calpains have been implicated in apoptotic cell death
, and appear to be an essential component of necrosis
.
In the brain, while μ-calpain is mainly located in the cell body and dendrite
s of neuron
s and to a lesser extent in axon
s and glial cell
s, m-calpain is found in glia and a small amount in axons. Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states.
influx after cerebrovascular accident (during the ischemic cascade
) or some types of traumatic brain injury
such as diffuse axonal injury
). Increase in concentration of calcium in the cell results in calpain activation, which leads to unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage. Excessively active calpain breaks down molecules in the cytoskeleton
such as spectrin
, microtubule
subunits, microtubule-associated protein
s, and neurofilament
s. It may also damage ion channel
s, other enzymes, cell adhesion molecule
s, and cell surface receptors. This can lead to degradation of the cytoskeleton and plasma membrane. Calpain may also break down sodium channels that have been damaged due to axonal stretch injury, leading to an influx of sodium
into the cell. This, in turn, leads to the neuron's
depolarization
and the influx of more Ca2+. A significant consequence of calpain activation is the development of cardiac contractile dysfunction that follows ischemic insult to the heart. Upon reperfusion of the ischemic myocardium, there is development of calcium overload or excess in the heart cell (cardiomyocytes). This increase in calcium leads to activation of calpain.
Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries. However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
-dependent, non-lysosomal
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
s (proteolytic enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS
Merops
Merops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1
CAPNS1
Calpain small subunit 1 is a protein that in humans is encoded by the CAPNS1 gene.-Further reading:...
, and the endogenous calpain-specific inhibitor, calpastatin
Calpastatin
Calpastatin is a protein that in humans is encoded by the CAST gene.-External Links:* The MEROPS online database for peptidases and their inhibitors: -Further reading:...
.
Discovery
The history of calpain originates in 1964, when calcium-dependent proteolytic activities caused by a “calcium-activated neutral protease” (CANP) were detected in brainBrain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
, lens of the eye and other tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
s. In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
. These activities were caused by an intracellular cysteine protease not associated with the lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
and having an optimum activity at neutral pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
, which clearly distinguished it from the cathepsin
Cathepsin
Cathepsins are proteases: proteins that break apart other proteins, found in many types of cells including those in all animals. There are approximately a dozen members of this family, which are distinguished by their structure, catalytic mechanism, and which proteins they cleave...
family of proteases. The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
on its substrates, highlighted calpain’s role as a regulatory, rather than a digestive protease. When the sequence of this enzyme became known, it was given the name “calpain”, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signalling protein, calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
, and the cysteine protease of papaya
Papaya
The papaya , papaw, or pawpaw is the fruit of the plant Carica papaya, the sole species in the genus Carica of the plant family Caricaceae...
, papain
Papain
Papain, also known as papaya proteinase I, is a cysteine protease enzyme present in papaya and mountain papaya .-Papain family:...
. Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed μ("mu")-calpain and m-calpain (a.k.a. calpain I and II), that differed primarily in their calcium requirements in vitro. Their names reflect the fact that they are activated by micro- and nearly millimolar concentrations of Ca2+ within the cell, respectively.
To date, these two isoforms remain the best characterised members of the calpain family. Structurally, these two heterodimeric
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
isoforms share an identical small (28k) subunit (CAPNS1
CAPNS1
Calpain small subunit 1 is a protein that in humans is encoded by the CAPNS1 gene.-Further reading:...
(formerly CAPN4)), but have distinct large (80k) subunits, known as calpain 1 and calpain 2 (each encoded by the CAPN1
CAPN1
Calpain-1 catalytic subunit is a protein that in humans is encoded by the CAPN1 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:...
and CAPN2
CAPN2
Calpain-2 catalytic subunit is a protein that in humans is encoded by the CAPN2 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:...
genes respectively).
Cleavage specificity
No specific amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence is uniquely recognized by calpains. Amongst protein substrates, tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
elements rather than primary amino acid sequences
Primary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
are likely responsible for directing cleavage to a specific substrate. Amongst peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
and small-molecule substrates, the most consistently reported specificity is for small, hydrophobic amino acids (e.g. leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
, valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
and isoleucine
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
) at the P2 position, and large hydrophobic amino acids (e.g. phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
and tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
) at the P1 position. Arguably, the best currently available fluorogenic calpain substrate is (EDANS
EDANS
EDANS is one of the most popular donors for developing FRET-based nucleic acid probes and protease substrates. EDANS is often paired with DABCYL or DABSYL....
)-Glu-Pro-Leu-Phe=Ala-Glu-Arg-Lys-(DABCYL), with cleavage occurring at the Phe=Ala bond.
Extended family
The Human Genome Project has revealed that there are more than a dozen other calpain isoforms, some with multiple splice variants. As the first calpain whose three-dimensional structure was determined, m-calpain is the type-protease for the C2 (calpain) family in the MEROPSMerops
Merops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
database.
| Gene | | Protein | Aliases | Tissue expression | Disease linkage |
|---|---|---|---|---|
| CAPN1 CAPN1 Calpain-1 catalytic subunit is a protein that in humans is encoded by the CAPN1 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:... |
Calpain 1 | Calpain-1 large subunit, Calpain mu-type | ||
| CAPN2 CAPN2 Calpain-2 catalytic subunit is a protein that in humans is encoded by the CAPN2 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:... |
Calpain 2 | Calpain-2 large subunit | ||
| CAPN3 CAPN3 Calpain-3 is a protein that in humans is encoded by the CAPN3 gene.-External links:* The MEROPS online database for peptidases and their inhibitors: ** LOVD mutation database:... |
Calpain 3 | skeletal muscle retina and lens specific | Limb Girdle muscular dystrophy 2A | |
| CAPN5 CAPN5 Calpain-5 is a protein that in humans is encoded by the CAPN5 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:... |
Calpain 5 | ubiquitous (high in colon, small intestine and testis) | might be linked to necrosis, as it is an ortholog of the C. elegans necrosis gene tra-3 |
|
| CAPN6 | Calpain 6 | CAPNX, Calpamodulin | ||
| CAPN7 | Calpain 7 | palBH | ubiquitous | |
| CAPN8 | Calpain 8 | exclusive to stomach mucosa and the GI track | might be linked to colon polyp formation | |
| CAPN9 CAPN9 Calpain-9 is a protein that in humans is encoded by the CAPN9 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:... |
Calpain 9 | exclusive to stomach mucosa and the GI track | might be linked to colon polyp formation | |
| CAPN10 CAPN10 Calpain-10 is a protein that in humans is encoded by the CAPN10 gene.-External Links:* The MEROPS online database for peptidases and their inhibitors:... |
Calpain 10 | susceptibility gene for type II diabetes | ||
| CAPN11 | Calpain 11 | testis | ||
| CAPN12 | Calpain 12 | ubiquitous but high in hair follicle | ||
| CAPN13 | Calpain 13 | testis and lung | ||
| CAPN14 | Calpain 14 | ubiquitous | ||
| SOLH | Calpain 15 | Sol H (homolog of the drosophila gene sol) | ||
| CAPNS1 CAPNS1 Calpain small subunit 1 is a protein that in humans is encoded by the CAPNS1 gene.-Further reading:... |
Calpain small subunit 1 | Calpain 4 | ||
| CAPNS2 | Calpain small subunit 2 |
Function
Although the physiological role of calpains are still poorly understood, they have been shown to be active participants in processes such as cell mobilityCell mobility
Cell mobility generally refers to motility, but may also refer to other ways of activation, such as cell differentiation and cell proliferation....
and cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression, as well as cell-type specific functions such as long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and cell fusion
Cell fusion
Cell fusion is an important cellular process that occurs during differentiation of muscle, bone and trophoblast cells, during embryogenesis, and during morphogenesis...
in myoblast
Myoblast
A myoblast is a type of embryonic progenitor cell that gives rise to muscle cells .The muscle cells can be skeletal muscle, smooth muscle, and cardiac muscle....
s. Under these physiological conditions, a transient and localized influx of calcium into the cell activates a small local population of calpains (for example, those close to Ca2+ channels), which then advance the signal transduction pathway by catalyzing the controlled proteolysis of its target proteins. Other reported roles of calpains are in cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
function, helping to regulate clotting and the diameter of blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s, and playing a role in memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
. Calpains have been implicated in apoptotic cell death
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, and appear to be an essential component of necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
.
In the brain, while μ-calpain is mainly located in the cell body and dendrite
Dendrite
Dendrites are the branched projections of a neuron that act to conduct the electrochemical stimulation received from other neural cells to the cell body, or soma, of the neuron from which the dendrites project...
s of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and to a lesser extent in axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
s and glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
s, m-calpain is found in glia and a small amount in axons. Calpain is also involved in skeletal muscle protein breakdown due to exercise and altered nutritional states.
Pathology
The structural and functional diversity of calpains in the cell is reflected in their involvement in the pathogenesis of a wide range of disorders. At least two well known genetic disorders and one form of cancer have been linked to tissue-specific calpains. When defective, the mammalian calpain 3 (also known as p94) is the gene product responsible for limb-girdle muscular dystrophy type 2A, calpain 10 has been identified as a susceptibility gene for type II diabetes mellitus, and calpain 9 has been identified as a tumour suppressor for gastric cancer. Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer’s disease, and cataract formation, as well as secondary degeneration resulting from acute cellular stress following myocardial ischemia, cerebral (neuronal) ischemia, traumatic brain injury and spinal cord injury. Excessive amounts of calpain can be activated due to Ca2+Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
influx after cerebrovascular accident (during the ischemic cascade
Ischemic cascade
The ischemic cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia . This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the...
) or some types of traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
such as diffuse axonal injury
Diffuse axonal injury
Diffuse axonal injury is one of the most common and devastating types of traumatic brain injury, meaning that damage occurs over a more widespread area than in focal brain injury. DAI, which refers to extensive lesions in white matter tracts, is one of the major causes of unconsciousness and...
). Increase in concentration of calcium in the cell results in calpain activation, which leads to unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage. Excessively active calpain breaks down molecules in the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
such as spectrin
Spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
, microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
subunits, microtubule-associated protein
Microtubule-associated protein
In cell biology, microtubule-associated proteins are proteins that interact with the microtubules of the cellular cytoskeleton.-Function:...
s, and neurofilament
Neurofilament
Neurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
s. It may also damage ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s, other enzymes, cell adhesion molecule
Cell adhesion molecule
Cell Adhesion Molecules are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix in the process called cell adhesion....
s, and cell surface receptors. This can lead to degradation of the cytoskeleton and plasma membrane. Calpain may also break down sodium channels that have been damaged due to axonal stretch injury, leading to an influx of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
into the cell. This, in turn, leads to the neuron's
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
depolarization
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
and the influx of more Ca2+. A significant consequence of calpain activation is the development of cardiac contractile dysfunction that follows ischemic insult to the heart. Upon reperfusion of the ischemic myocardium, there is development of calcium overload or excess in the heart cell (cardiomyocytes). This increase in calcium leads to activation of calpain.
Therapeutic inhibitors
The exogenous regulation of calpain activity is therefore of interest for the development of therapeutics in a wide array of pathological states. As a few of the many examples supporting the therapeutic potential of calpain inhibition in ischemia, calpain inhibitor AK275 protected against focal ischemic brain damage in rats when administered after ischemia, and MDL28170 significantly reduced the size of damaged infarct tissue in a rat focal ischemia model. There are also known calpain inhibitors with neuroprotective effects: PD150606, SJA6017, ABT-705253,and SNJ-1945.Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries. However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.
External links
- CaMPDB, Calpain for Modulatory Proteolysis Database
- The Calpain Family of Proteases. (2001). University of Arizona.
- Calpain Info with links in the Cell Migration Gateway
- Alzheimers and calpain protease, PMAP The Proteolysis MapThe Proteolysis MapThe Proteolysis MAP is an integrated web resource focused on proteases.-Rationale:PMAP is to aid the protease researchers in reasoning about proteolytic networks and metabolic pathways.-History and funding:...
-animation.