S100A10
Encyclopedia
S100-A10, also known as p11, is a protein
that is encoded by the S100A10 gene
in humans and the S100a10 gene in other species. S100-A10 is a member of the S100
family of proteins containing two EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells. They regulate a number of cellular processes such as cell cycle progression and differentiation. The S100 protein is implicated in exocytosis
and endocytosis
by reorganization of F-actin.
The p11 protein is linked with the transport of neurotransmitter
s. Found in the brain of humans and other mammals, it has been implicated in the regulation of mood. In addition, due to its interaction with serotonin
-signaling proteins and its correlation with symptoms of mood disorder
s, p11 is a new potential target for drug therapy.
currently known, with most S100 genes (S100A1 to S100A16).
. The homodimer or heterotetramer can, in turn, dimerize through formation of two disulfide bond
s (see figure to the left). The p11 monomer is an asymmetric protein composed of four alpha helices. The dimerized form of the protein is created by packing between the H1 and H4 helices in an antiparallel arrangement with the hydrophobic regions residing in the core.
The structure of p11 is classified by a pair of the helix-loop-helix motif, also known as the EF-hand-type that recognizes and binds calcium ions. This is common to all known S-100 proteins. The EF-hand types, united by an anti-parallel beta-strand between loops L1 and L3, are located on the same side of the molecule, opposite the N-and C-termini. As a member of the S-100 family, its structure resembles that of the S-100A1 and S-100B proteins. This class of proteins has been implicated in the regulation of cytoskeleton assembly, cytosolic enzymes, and membrane dynamics.
P11's involvement with the cytoskeleton may aid the transport of other proteins throughout the cell and to the cell membrane. Unlike other S-100 proteins, the second EF-hand of protein p11 is incapable of binding calcium due to a series of mutations caused by deletions and substitutions. Annexin II, which is attracted to negatively charged phospholipids, binds to p11 at the Ca2+ binding site. In addition, Annexin II has been implicated in membrane-cytoskeleton interactions and in regulations of ion currents and substances across the membrane. P11 and annexin II form a heterotetrameric protein complex that imitates the structure and function of S-100 proteins activated by the binding of calcium. This tetrameric complex is more stable than the p11 dimer, therefore the overexpression of the annexin II gene results in higher levels of p11 protein.
Ion channel
s are among the several proteins that are transported through the interaction with p11. Some of these proteins include Nav1.8
, TRPV5
, TRPV6
, TASK-1
, and ASIC1a
. Nav1.8 is a tetrodotoxin
-resistant sodium channel that replaces lost sodium after cell damage. Increased expression of these channels alters the magnitude of the sodium current across the membrane. TRPV5 and TRPV6 are transient receptor potential channels selective for Ca+ and Mg2+ ions. TASK-1 is a two-pore domain K+ channel TWIK-related acid-sensitive K (TASK). P11 can also function as a retention factor, preventing TASK-1 from leaving the endoplasmic reticulum
. ASIC1a is an acid-sensing ion channel involved in the pain sensory pathway, which is regulated by p11.
Although the exact mechanism is unclear, p11 protein has shown to be essential in the regulation of serotonin signaling in the brain. Serotonin (5-hydroxytryptamine or 5-HT), is a neurotransmitter found in the central and peripheral nervous systems. It is involved in mechanisms responsible for memory formation and learning, but is most known for its role in the regulation muscle contraction, appetite, sleep, and mood. Varying levels of serotonin found in the brain are associated with the development of mood disorders, such as clinical depression. P11 interacts with the serotonin receptor proteins, 5-HT receptor
s such as 5-HT1B
, modulating the receptor signal transduction pathways activated by the binding of serotonin. P11 also recruits the cell surface expression of the 5-HT4
receptor, increasing its concentration at the synapse. This results in more rapid serotonin-dependent activities. 5-HT4 is involved in the regulation of kinase activity in the central nervous system, phosphorylating target proteins, and facilitating endosomal activities. P11 is coexpressed with 5-HT4 mRNA and its protein in parts of the brain associated with depression, suggesting that their functions are linked and influence mood.
Protein p11 can also be presented on the cell surface as a receptor for tissue-type plasminogen activator (tPA
) and plasminogen. Plasmin production by many cells is dependent on p11.
with TRPV5
, TRPV6
, TASK-1
, ASIC1a
, CTSB
, BAD
, KCNK3
, UBC
and ANXA2
.
There is a specificity in the interaction between p11 and 5-HT1B. In a two-hybrid screen using twenty six out of 29 double-positive prey clones containing the gene encoding p11. This study showed that p11 interacted with 5-HT1B receptors but not with 5-HT1A
, 5-HT2A
, 5-HT5A
, 5-HT6
, dopamine D1
or D2
receptors, two irrelevant baits (C{Delta}115 and pRP21), or the empty plasmid. The specific interaction has been verified in three other ways: In HeLa cells
and brain tissue p11 was found to coimmunoprecipitate with 5-HT1B receptors; Immunofluorescence
studies show colocalization between p11 and 5-HT1B receptors at the cell surface; and distribution of p11 mRNA in the brain resembles that of 5-HT1B receptor mRNA.
The table below shows the proteins that interact with p11 and the functional role of p11 in these interactions
of SerII on the annexin II molecule by protein kinase C
(PKC). This phosporylation hinders the complex's ability to bind to certain target molecules. Protein Kinase A (PKA) reverses the effects of PKC by activating a phosphatase, which reactivates the complex through dephosphorylation
.
, bipolar disorder
, ADD
, ADHD, and Schizophrenia
.
The p11 protein has been intimately linked to mood disorders, to be specific, depression, due to its role in serotonin systems via its interactions with serotonin 5-HT receptors. Serotonin affects diverse systems including the cardiovascular, renal, immune, and gastrointestinal systems. Current research focuses on the neurotransmitter's relationship with mood-regulation.
Under experimentation, mice deficient in the p11 protein display depression-like behaviors. Knockout experiments in which the gene coding for protein p11 was deleted from the mouse genome caused them to show signs of depression. This is also observed in humans. On the other hand, those with sufficient amount of p11 protein behave normally. When mice that showed depressive symptoms were administered anti-depressant drugs, their levels of p11 were found to increase at the same rate, as antidepressants affected their behavioral changes. In addition, post-mortem comparisons of brain tissues showed much lower levels of p11 in depressed compared to control subjects. Levels of p11 have been found to be substantially lower in depressed humans and helpless mice, which suggests that altered p11 levels may be involved in the development of depression-like symptoms.
s), a very successful class of drugs, are known to increase the amount of serotonin available to brain cells quite rapidly. Despite this, their therapeutic effects take a period of several weeks to months. Recent studies show that protein p11 increases the concentration of the serotonin 5-HT receptors at neuronal synapses, thereby rendering serotonin signaling much more efficient. The interaction with the serotonin 1b receptor (5-HT1B) and p11 can be summarized as follows: When p11 levels increases, the number of 5-HT1B receptors on the cell surface increase proportionately. An increase in the number of 5-HT1B receptors on the surface of the neuron increase the effectiveness of serotonin communication across the synapse. On the other hand, when p11 levels decrease, fewer 5-HT1B receptors migrate from inside the neuron to the cell membrane at the synaptic cleft, thus lowering the efficiency with which serotonin signaling can occur across the synapse. These findings suggest that, although the serotonin levels are immediately introduced via medication, the period of time within which the medicine alleviates the patient’s depression most likely relies on other regulatory proteins. Thus, given protein p11’s interaction with serotonin 5-HT receptors and the increasing evidence of the protein’s correlation to mood disorders, this protein has been identified as a target for research in the development of future antidepressants.
Treatment with antidepressants (a tricyclic and monoamine oxidase inhibitor) and electroconvulsive therapy
(ECT) caused an increase in the amount of p11 in the brain of these mice - the same biochemical change. The levels of the p11 protein in humans and mice with symptoms of depression were substantially lower in comparison to the levels of p11 in non-depressed animals. Leading researcher Paul Greengard
and his colleagues hypothesized that increasing p11 levels would result in the mice exhibiting antidepressant-like behaviors, and the opposite if p11 protein levels were reduced. They used a test that is used to measure antidepressant-like activity to affirm this hypothesis. In their findings, over-expressed p11 genes, compared to the control mice, had increased mobility and more 5-HT1B receptors at the cell surface, which made possible more serotonin transmission. When researchers "knocked out" the p11 gene in mice, they found that the knockout mice had fewer receptors at the cell surface, reduced serotonin signaling, reduced responsiveness to sweet reward, and decreased mobility, behaviors all characteristic of depression-like behaviors. Also, the 5-HT1B receptors of p11 knockout mice were less responsive to serotonin and antidepressant drugs compared to those of control mice, which further implicates p11 in the main action of antidepressant medications. Antidepressant manipulations increase the p11 levels, whereas depressant manipulations reduce it. Therefore, in order to achieve an anti-depression effect, antidepressant medications should focus on the main action of the p11 proteins and increase levels of the protein.
(Celexa), a serotonin reuptake inhibitor. If successful, a more personalized treatment of MDD will be available in the future.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that is encoded by the S100A10 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in humans and the S100a10 gene in other species. S100-A10 is a member of the S100
S-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
family of proteins containing two EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells. They regulate a number of cellular processes such as cell cycle progression and differentiation. The S100 protein is implicated in exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
and endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
by reorganization of F-actin.
The p11 protein is linked with the transport of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s. Found in the brain of humans and other mammals, it has been implicated in the regulation of mood. In addition, due to its interaction with serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
-signaling proteins and its correlation with symptoms of mood disorder
Mood disorder
Mood disorder is the term designating a group of diagnoses in the Diagnostic and Statistical Manual of Mental Disorders classification system where a disturbance in the person's mood is hypothesized to be the main underlying feature...
s, p11 is a new potential target for drug therapy.
Gene
The S100 gene family includes at least 13 members that are located as a cluster on chromosome 1q21. In humans, 19 family members arecurrently known, with most S100 genes (S100A1 to S100A16).
Structure
The p11 protein can be found as a free monomer, a homodimer, or a heterotetramer composed of a p11 dimer complex with two molecules of annexin IIAnnexin A2
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.Annexin 2 is involved in diverse cellular processes such as cell motility , linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and...
. The homodimer or heterotetramer can, in turn, dimerize through formation of two disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s (see figure to the left). The p11 monomer is an asymmetric protein composed of four alpha helices. The dimerized form of the protein is created by packing between the H1 and H4 helices in an antiparallel arrangement with the hydrophobic regions residing in the core.
The structure of p11 is classified by a pair of the helix-loop-helix motif, also known as the EF-hand-type that recognizes and binds calcium ions. This is common to all known S-100 proteins. The EF-hand types, united by an anti-parallel beta-strand between loops L1 and L3, are located on the same side of the molecule, opposite the N-and C-termini. As a member of the S-100 family, its structure resembles that of the S-100A1 and S-100B proteins. This class of proteins has been implicated in the regulation of cytoskeleton assembly, cytosolic enzymes, and membrane dynamics.
P11's involvement with the cytoskeleton may aid the transport of other proteins throughout the cell and to the cell membrane. Unlike other S-100 proteins, the second EF-hand of protein p11 is incapable of binding calcium due to a series of mutations caused by deletions and substitutions. Annexin II, which is attracted to negatively charged phospholipids, binds to p11 at the Ca2+ binding site. In addition, Annexin II has been implicated in membrane-cytoskeleton interactions and in regulations of ion currents and substances across the membrane. P11 and annexin II form a heterotetrameric protein complex that imitates the structure and function of S-100 proteins activated by the binding of calcium. This tetrameric complex is more stable than the p11 dimer, therefore the overexpression of the annexin II gene results in higher levels of p11 protein.
Function
P11 is an integral part of cellular structural scaffolding that interacts with plasma membrane proteins through its association with annexin II. Recently, it was discovered to form a complex with annexin I though the mechanism remains unknown. It works together with cytosolic and peripheral membrane-associated proteins such as AHNAK in the development of the intracellular membrane. P11 has been implicated in the transportation of proteins involved in mood regulation, nociception, and cell polarization. It is found in cell types throughout the body though it is located predominantly in the lungs and kidneys. It is involved in the trafficking of proteins to the plasma membrane and can be expressed on the cell surface as a receptor. Many of the transported proteins are cell surface receptors in signal transduction pathways and ion channels. P11 facilitates nociception, Ca2+ uptake, and cell polaraization. Complexed with the annexin II, p11 binds receptor and channel proteins and guides them to the cell surface, resulting in increased membrane localization and consequent magnified functional expression of these proteins.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 are among the several proteins that are transported through the interaction with p11. Some of these proteins include Nav1.8
SCN10A
Sodium channel, voltage gated, type X, alpha subunit also known as SCN10A or Nav1.8 is a protein which in humans is encoded by the SCN10A gene.Nav1.8 is a sodium channel subunit.-Function:...
, TRPV5
TRPV5
Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the...
, TRPV6
TRPV6
TRPV6 is a membrane calcium channel which is responsible for the first step in calcium absorption in the intestine. It was first named CAT1, or ECaC2, and has been described in the intestine in several species, including humans. It is located in the apical brush-border membrane of the intestinal...
, TASK-1
KCNK3
Potassium channel subfamily K member 3 is a protein that in humans is encoded by the KCNK3 gene.-Interactions:KCNK3 has been shown to interact with YWHAB and S100A10.- External links :...
, and ASIC1a
ACCN2
Amiloride-sensitive cation channel 2, neuronal is a protein that in humans is encoded by the ACCN2 gene.- Function :This gene encodes a member of the degenerin/epithelial sodium channel superfamily...
. Nav1.8 is a tetrodotoxin
Tetrodotoxin
Tetrodotoxin, also known as "tetrodox" and frequently abbreviated as TTX, sometimes colloquially referred to as "zombie powder" by those who practice Vodou, is a potent neurotoxin with no known antidote. There have been successful tests of a possible antidote in mice, but further tests must be...
-resistant sodium channel that replaces lost sodium after cell damage. Increased expression of these channels alters the magnitude of the sodium current across the membrane. TRPV5 and TRPV6 are transient receptor potential channels selective for Ca+ and Mg2+ ions. TASK-1 is a two-pore domain K+ channel TWIK-related acid-sensitive K (TASK). P11 can also function as a retention factor, preventing TASK-1 from leaving the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. ASIC1a is an acid-sensing ion channel involved in the pain sensory pathway, which is regulated by p11.
Although the exact mechanism is unclear, p11 protein has shown to be essential in the regulation of serotonin signaling in the brain. Serotonin (5-hydroxytryptamine or 5-HT), is a neurotransmitter found in the central and peripheral nervous systems. It is involved in mechanisms responsible for memory formation and learning, but is most known for its role in the regulation muscle contraction, appetite, sleep, and mood. Varying levels of serotonin found in the brain are associated with the development of mood disorders, such as clinical depression. P11 interacts with the serotonin receptor proteins, 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
s such as 5-HT1B
5-HT1B receptor
5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.-Tissue distribution and function:...
, modulating the receptor signal transduction pathways activated by the binding of serotonin. P11 also recruits the cell surface expression of the 5-HT4
5-HT4 receptor
5-hydroxytryptamine receptor 4 is a protein that in humans is encoded by the HTR4 gene.- Location :The receptor is located in the alimentary tract, urinary bladder, heart and adrenal gland as well as the central nervous system ....
receptor, increasing its concentration at the synapse. This results in more rapid serotonin-dependent activities. 5-HT4 is involved in the regulation of kinase activity in the central nervous system, phosphorylating target proteins, and facilitating endosomal activities. P11 is coexpressed with 5-HT4 mRNA and its protein in parts of the brain associated with depression, suggesting that their functions are linked and influence mood.
Protein p11 can also be presented on the cell surface as a receptor for tissue-type plasminogen activator (tPA
Tissue plasminogen activator
Tissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...
) and plasminogen. Plasmin production by many cells is dependent on p11.
Interactions
S100A10 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TRPV5
TRPV5
Transient receptor potential cation channel subfamily V member 5 is a protein that in humans is encoded by the TRPV5 gene.TRPV5 is mainly expressed in kidney epithelial cells, where it plays an important role in the reabsorption of Ca2+.. Genetic deletion of TRPV5 in mice leads to Ca2+ loss in the...
, TRPV6
TRPV6
TRPV6 is a membrane calcium channel which is responsible for the first step in calcium absorption in the intestine. It was first named CAT1, or ECaC2, and has been described in the intestine in several species, including humans. It is located in the apical brush-border membrane of the intestinal...
, TASK-1
KCNK3
Potassium channel subfamily K member 3 is a protein that in humans is encoded by the KCNK3 gene.-Interactions:KCNK3 has been shown to interact with YWHAB and S100A10.- External links :...
, ASIC1a
ACCN2
Amiloride-sensitive cation channel 2, neuronal is a protein that in humans is encoded by the ACCN2 gene.- Function :This gene encodes a member of the degenerin/epithelial sodium channel superfamily...
, CTSB
Cathepsin B
Cathepsin B is an enzymatic protein belonging to the peptidase families. In humans, it is coded by the CTSB gene.- Function :...
, BAD
Bcl-2-associated death promoter
The Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family...
, KCNK3
KCNK3
Potassium channel subfamily K member 3 is a protein that in humans is encoded by the KCNK3 gene.-Interactions:KCNK3 has been shown to interact with YWHAB and S100A10.- External links :...
, UBC
Ubiquitin C
Ubiquitin is a protein that in humans is encoded by the UBC gene.-Interactions:Ubiquitin C has been shown to interact with SCNN1A, SCNN1G, Parkin , P70-S6 Kinase 1, TRAF6, HDAC3, SFPQ, S100A10, Mothers against decapentaplegic homolog 3, NOTCH1, HIF1A, Epidermal growth factor receptor, E2F1,...
and ANXA2
Annexin A2
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.Annexin 2 is involved in diverse cellular processes such as cell motility , linkage of membrane-associated protein complexes to the actin cytoskeleton, endocytosis, fibrinolysis, ion channel formation, and...
.
There is a specificity in the interaction between p11 and 5-HT1B. In a two-hybrid screen using twenty six out of 29 double-positive prey clones containing the gene encoding p11. This study showed that p11 interacted with 5-HT1B receptors but not with 5-HT1A
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
, 5-HT2A
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
, 5-HT5A
5-HT5A receptor
5-hydroxytryptamine receptor 5A, also known as HTR5A, is a protein which in humans is encoded by the HTR5A gene.- Function :...
, 5-HT6
5-HT6 receptor
The 5-HT6 receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gs/Go and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.-Distribution:The 5-HT6 receptor is...
, dopamine D1
Dopamine receptor D1
Dopamine receptor D1, also known as DRD1, is a protein that in humans is encoded by the DRD1 gene.- Function :This gene encodes the D1 subtype of the dopamine receptor. The D1 subtype is the most abundant dopamine receptor in the central nervous system. This G-protein-coupled receptor stimulates...
or D2
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
receptors, two irrelevant baits (C{Delta}115 and pRP21), or the empty plasmid. The specific interaction has been verified in three other ways: In HeLa cells
HeLa
A HeLa cell is a cell type in an immortal cell line used in scientific research. It is the oldest and most commonly used human cell line. The line was derived from cervical cancer cells taken on February 8, 1951 from Henrietta Lacks, a patient who eventually died of her cancer on October 4, 1951...
and brain tissue p11 was found to coimmunoprecipitate with 5-HT1B receptors; Immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
studies show colocalization between p11 and 5-HT1B receptors at the cell surface; and distribution of p11 mRNA in the brain resembles that of 5-HT1B receptor mRNA.
The table below shows the proteins that interact with p11 and the functional role of p11 in these interactions
Table 1
| Interactor | Biological function of P11 | Reference |
|---|---|---|
| Annexin 2 | Regulation of endosomal functions | |
| 5-HT1B receptor 5-HT1B receptor 5-hydroxytryptamine receptor 1B also known as the 5-HT1B receptor is a protein that in humans is encoded by the HTR1B gene. The 5-HT1B receptor is a 5-HT receptor subtype.-Tissue distribution and function:... |
Localization of 5-HT1B receptors at the cell surface | |
| NaV1.8 sodium channel | Increase of NaV1.8 channels at the plasma membrane | |
| TASK-1 potassium channel | Regulation of TASK-1 channels at the plasma membrane | |
| ASIC-1 channels | Increase of ASIC channels at the plasma membrane | |
| TRPV5/TRPV6 channels | Increase of TRPV5/TRPV6 channels at the plasma membrane | |
| NS3 | Mediation of virus release | |
| Cytosolic phospholipase A2 | Reduced arachidonic acid release | |
| BAD Bcl-2-associated death promoter The Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family... |
Inhibition of pro-apoptotic effect | |
Regulation of Protein Activity
The p11 and annexin II complex is regulated by the phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of SerII on the annexin II molecule by protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC). This phosporylation hinders the complex's ability to bind to certain target molecules. Protein Kinase A (PKA) reverses the effects of PKC by activating a phosphatase, which reactivates the complex through dephosphorylation
Dephosphorylation
Dephosphorylation is the essential process of removing phosphate groups from an organic compound by hydrolysis. Its opposite is phosphorylation...
.
Regulation of Transcription
Current experiments on animals have shown that various factors and physiological stimuli have been successful in regulating the levels of p11 protein transcription. Some of these factors are shown in the table below.Table 2
| Factor | Biological system | Reference |
|---|---|---|
| Dexamethasone Dexamethasone Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant... |
BEAS and HeLa HeLa A HeLa cell is a cell type in an immortal cell line used in scientific research. It is the oldest and most commonly used human cell line. The line was derived from cervical cancer cells taken on February 8, 1951 from Henrietta Lacks, a patient who eventually died of her cancer on October 4, 1951... cells |
|
| Transforming growth factor-α | RGM-1 cells | |
| Epidermal growth factor Epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR... |
depolarization BEAS and HeLa cells | |
| Nitric Oxide Nitric oxide Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry... donors |
BEAS and HeLa cells | |
| Interferon-gamma Interferon-gamma Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs... |
BEAS cells | |
| Vitamin D Vitamin D Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate .... |
mouse kidney Kidney The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and... |
|
| Retinoic acid Retinoic acid Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans... |
BEAS cells | |
| nerve growth factor Nerve growth factor Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described... |
PC12 cells PC12 cells PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla. PC12 cells stop dividing and terminally differentiate when treated with nerve growth factor... , rat dorsal root ganglion Dorsal root ganglion In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:... |
|
| imipramine Imipramine Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group... |
mouse frontal cortex | |
| tranylcypromine Tranylcypromine Tranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase... |
mouse frontal cortex | |
| Electroconvulsive treatment | rat frontal cortex | |
| Sciatic nerve Sciatic nerve The sciatic nerve is a large nerve fiber in humans and other animals. It begins in the lower back and runs through the buttock and down the lower limb... lesion Lesion A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :... |
rat | |
| Experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis Experimental autoimmune encephalomyelitis, sometimes Experimental Allergic Encephalomyelitis is an animal model of brain inflammation. It is an inflammatory demyelinating disease of the central nervous system... |
rat cerebellum Cerebellum The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established... |
Depression
Depression is a widespread, debilitating disease affecting persons of all ages and backgrounds. Depression is characterized by a plethora of emotional and physiological symptoms including feelings of sadness, hopelessness, pessimism, guilt, a general loss of interest in life, and a sense of reduced emotional well-being or low energy. Very little is known about the underlying pathophysiology of clinical depression and other related mood-disorders including anxietyAnxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, ADD
ADHD predominantly inattentive
ADHD predominantly inattentive is one of the three subtypes of Attention-deficit hyperactivity disorder . While ADHD-PI is sometimes still called "attention deficit disorder" by the general public, these older terms were formally changed in 1994 in the new Diagnostic and Statistical Manual of...
, ADHD, and Schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
.
The p11 protein has been intimately linked to mood disorders, to be specific, depression, due to its role in serotonin systems via its interactions with serotonin 5-HT receptors. Serotonin affects diverse systems including the cardiovascular, renal, immune, and gastrointestinal systems. Current research focuses on the neurotransmitter's relationship with mood-regulation.
Under experimentation, mice deficient in the p11 protein display depression-like behaviors. Knockout experiments in which the gene coding for protein p11 was deleted from the mouse genome caused them to show signs of depression. This is also observed in humans. On the other hand, those with sufficient amount of p11 protein behave normally. When mice that showed depressive symptoms were administered anti-depressant drugs, their levels of p11 were found to increase at the same rate, as antidepressants affected their behavioral changes. In addition, post-mortem comparisons of brain tissues showed much lower levels of p11 in depressed compared to control subjects. Levels of p11 have been found to be substantially lower in depressed humans and helpless mice, which suggests that altered p11 levels may be involved in the development of depression-like symptoms.
Treatment
Most of the current drugs and treatments for depression and anxiety increase levels of serotonin transmission among neurons. Selective Serotonin Reuptake Inhibitors (SSRISelective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s), a very successful class of drugs, are known to increase the amount of serotonin available to brain cells quite rapidly. Despite this, their therapeutic effects take a period of several weeks to months. Recent studies show that protein p11 increases the concentration of the serotonin 5-HT receptors at neuronal synapses, thereby rendering serotonin signaling much more efficient. The interaction with the serotonin 1b receptor (5-HT1B) and p11 can be summarized as follows: When p11 levels increases, the number of 5-HT1B receptors on the cell surface increase proportionately. An increase in the number of 5-HT1B receptors on the surface of the neuron increase the effectiveness of serotonin communication across the synapse. On the other hand, when p11 levels decrease, fewer 5-HT1B receptors migrate from inside the neuron to the cell membrane at the synaptic cleft, thus lowering the efficiency with which serotonin signaling can occur across the synapse. These findings suggest that, although the serotonin levels are immediately introduced via medication, the period of time within which the medicine alleviates the patient’s depression most likely relies on other regulatory proteins. Thus, given protein p11’s interaction with serotonin 5-HT receptors and the increasing evidence of the protein’s correlation to mood disorders, this protein has been identified as a target for research in the development of future antidepressants.
Treatment with antidepressants (a tricyclic and monoamine oxidase inhibitor) and electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
(ECT) caused an increase in the amount of p11 in the brain of these mice - the same biochemical change. The levels of the p11 protein in humans and mice with symptoms of depression were substantially lower in comparison to the levels of p11 in non-depressed animals. Leading researcher Paul Greengard
Paul Greengard
Paul Greengard is an American neuroscientist best known for his work on the molecular and cellular function of neurons. In 2000, Greengard, Arvid Carlsson and Eric Kandel were awarded the Nobel Prize for Physiology or Medicine for their discoveries concerning signal transduction in the nervous...
and his colleagues hypothesized that increasing p11 levels would result in the mice exhibiting antidepressant-like behaviors, and the opposite if p11 protein levels were reduced. They used a test that is used to measure antidepressant-like activity to affirm this hypothesis. In their findings, over-expressed p11 genes, compared to the control mice, had increased mobility and more 5-HT1B receptors at the cell surface, which made possible more serotonin transmission. When researchers "knocked out" the p11 gene in mice, they found that the knockout mice had fewer receptors at the cell surface, reduced serotonin signaling, reduced responsiveness to sweet reward, and decreased mobility, behaviors all characteristic of depression-like behaviors. Also, the 5-HT1B receptors of p11 knockout mice were less responsive to serotonin and antidepressant drugs compared to those of control mice, which further implicates p11 in the main action of antidepressant medications. Antidepressant manipulations increase the p11 levels, whereas depressant manipulations reduce it. Therefore, in order to achieve an anti-depression effect, antidepressant medications should focus on the main action of the p11 proteins and increase levels of the protein.
Future Clinical trials
At the current time, a study by the National Institutes of Health Clinical Center (CC) is recruiting participants for a study that will compare levels of p11 protein in people with and without Major Depressive Disorder (MDD) and determine whether p11 levels in patients are affected by treatment with citalopramCitalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa), a serotonin reuptake inhibitor. If successful, a more personalized treatment of MDD will be available in the future.
External links
- Associated story on U.S. National Public Radio