Inositol triphosphate
Encyclopedia
Inositol trisphosphate or inositol 1,4,5-trisphosphate (also commonly known as triphosphoinositol; abbreviated InsP3 or IP3), together with diacylglycerol
(DAG), is a secondary messenger molecule used in signal transduction
and lipid signaling
in biological cell
s. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell. It is made by hydrolysis
of phosphatidylinositol 4,5-bisphosphate
(PIP2), a phospholipid
that is located in the plasma membrane, by phospholipase C
(PLC).
with a molecular mass
of 420.10 g/mol. Its empirical formula
is C6H15O15P3. It is composed of an inositol
ring with three phosphate
groups bound at the 1, 4, and 5 carbon positions, and three hydroxyl
groups bound at positions 2, 3, and 6.
. Phosphorous atoms can bind three oxygen atoms with single bonds and a fourth oxygen atom using a double bond. The pH of the solution, and thus the form of the phosphate group determines its ability to bind to other molecules. The binding of phosphate groups to the inositol ring is accomplished by phosphor-ester binding (see phosphoric acids and phosphates
). This bond involves combining a hydroxyl
group from the inositol ring and a free phosphate group through a dehydration reaction
. Considering that the average physiological pH is approximately 7.4, the main form of the phosphate groups bound to the inositol ring in vivo
is PO42-. This gives IP3 a net negative charge, which is important in allowing it to dock to its receptor, through binding of the phosphate groups to positively charged residues on the receptor. IP3 has three hydrogen bond
donors in the form of its three hydroxyl groups. The hydroxyl group on the 6th carbon atom in the inositol ring is also involved in IP3 docking.
in the early 1990s.. Studies focused on the N-terminus side of the IP3 receptor. In 1997 researchers localized the region of the IP3 receptor involved with binding of IP3 to between amino acid
residues 226 and 578 in 1997. Considering that IP3 is a negatively charged molecule, positively charged amino acids such as Arginine
and Lysine
, were believed to be involved. Two Arginine residues at position 265 and 511 and one Lysine residue at position 508 were found to be key in IP3 docking. Using a modified form of IP3, it was discovered that all three phosphate groups, phosphates at the 4th and 5th positions more extensively than the one at the 1st position, as well as the hydroxyl group at position 6 of the inositol ring interact with the receptor.
was made by Mabel R. Hokin (1924-2003) and her then husband Lowell E. Hokin in 1953, when they discovered that radioactive 32P phosphate was incorporated into the phosphatidylinositol
of pancreas
slices when stimulated with acetylcholine
. Up until then phospholipids were believed to be innate structures only used by cells as building blocks for construction of the plasma membrane.
Over the next 20 years, little was discovered about the importance of PIP2 metabolism
in terms of cell signalling, until the mid-1970s when Robert H. Mitchell hypothesized a connection between the catabolism
of PIP2 and increases in intracellular
calcium
(Ca2+ levels. He hypothesized that receptor-activated hydrolysis of PIP2 produced a molecule that caused increases in intracellular calcium mobilization. This idea was researched extensively by Mitchell and his colleagues, who in 1981 were able to show that PIP2 is hydrolyzed into DAG and IP3 by a then unknown phosphodiesterase
. In 1984 it was discovered that IP3 acts as a secondary messenger that is capable of traveling through the cytoplasm
to the endoplasmic reticulum
(ER), where it stimulates the release of calcium into the cytoplasm.
Further research provided valuable information on the IP3 pathway, such as the discovery in 1986 that one of the many roles of the calcium released by IP3 is to work with DAG to activate protein kinase C
(PKC). As well, it was discovered in 1989 that PLC is the phosphodiesterase responsible for hydrolyzing PIP2 into DAG and IP3. Today the IP3 signalling pathway is well mapped out and is known to be important in regulating a variety of calcium-dependent cell signalling pathways.
Increases in the intracellular Ca2+ concentrations is often a result of IP3 activation. When a ligand
binds to a G protein-coupled receptor
(GPCR) that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme
PLC-β, which results in the cleavage of PIP2 into IP3 and DAG .
If a receptor tyrosine kinase
(RTK) is involved in activating the pathway, the isozyme PLC-γ has [tyrosine] residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP2 into DAG and IP3. This occurs in cells that are capable of responding to growth factors such as insulin
, because the growth factors are the ligands responsible for activating the RTK.
IP3 is a soluble molecule and is capable of diffusing through the cytoplasm to the ER, or the sarcoplasmic reticulum (SR) in the case of muscle
cells, once produced by PLC. Once at the ER, IP3 is able to bind to a the Ins3PR receptor on a ligand-gated Ca2+ channel that is found on the surface of the ER. The binding of IP3 to InsP3R triggers the opening of the Ca2+ channel and the release of Ca2+ into the cytoplasm . In muscle cells this increase in Ca2+ activates the ryanodine receptor
-operated channel on the SR, results in further increases in Ca2+ through a process known as calcium-induced calcium release. IP3 may also activate Ca2+ channels on the cell membrane indirectly by increasing the intracellular Ca2+ concentration .
s and to regulate cell proliferation and other cellular reactions.
In smooth muscle cells, for example, the increase in concentration of cytoplasmic Ca2+ results in the contraction of the muscle cell.
In the nervous system, IP3 serves as a second messenger, with the cerebellum
containing the highest concentration of IP3 receptors. There is evidence that IP3 receptors play an important role in the induction of plasticity in cerebellar Purkinje cells.
is an incurable genetic disorder
that occurs when neurons in the brain
degenerate . Huntington’s disease primarily affects striatal medium spiny neurons (MSN). GABAergic MSNs make up more than 95% of all neurons in the striatum
. Huntington’s disease occurs when the cytosolic protein Huntingtin
(Htt) has an additional 35 glutamine
residues added to its amino terminal region. This modified form of Htt is called Httexp. Httexp makes Type 1 IP3 receptors more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in the cytosolic and mitochondrial concentrations of Ca2+. This increase in Ca2+ is thought to be the cause of GABA
ergic MSN degradation
(APP) genes
. All of the mutated forms of these genes observed to date have been found to cause abnormal Ca2+ signaling in the ER. The functions of PS1 are not yet known, but mutations in PS1 have been shown to increase IP3-mediated Ca2+ release from the ER in several animal models. Calcium channel blockers have been used to treat Alzheimer’s disease with some success, and the use of lithium to decrease IP3 turnover has also been suggested as a possible method of treatment .
Diglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
(DAG), is a secondary messenger molecule used in signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
and lipid signaling
Lipid signaling
Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses...
in biological 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....
s. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell. It is made by hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate
Phosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
(PIP2), a phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
that is located in the plasma membrane, by phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC).
Chemical Formula and Molecular Weight
IP3 is a polyatomic ionPolyatomic ion
A polyatomic ion, also known as a molecular ion, is a charged species composed of two or more atoms covalently bonded or of a metal complex that can be considered as acting as a single unit in the context of acid and base chemistry or in the formation of salts. The prefix "poly-" means "many," in...
with a molecular mass
Molecular mass
The molecular mass of a substance is the mass of one molecule of that substance, in unified atomic mass unit u...
of 420.10 g/mol. Its empirical formula
Empirical formula
In chemistry, the empirical formula of a chemical compound is the simplest positive integer ratio of atoms of each element present in a compound. An empirical formula makes no reference to isomerism, structure, or absolute number of atoms. The empirical formula is used as standard for most ionic...
is C6H15O15P3. It is composed of an inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
ring with three phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
groups bound at the 1, 4, and 5 carbon positions, and three hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
groups bound at positions 2, 3, and 6.
Chemical proprieties of phosphate group and IP3
Phosphate groups can exist in three different forms depending on a solution’s pHPH
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...
. Phosphorous atoms can bind three oxygen atoms with single bonds and a fourth oxygen atom using a double bond. The pH of the solution, and thus the form of the phosphate group determines its ability to bind to other molecules. The binding of phosphate groups to the inositol ring is accomplished by phosphor-ester binding (see phosphoric acids and phosphates
Phosphoric acids and Phosphates
There are various kinds of phosphoric acids and phosphates. Of the many phosphorus oxoacids, the phosphoric acids constitute the largest and most diverse group. The simplest phosphoric acid series begins with monophosphoric acid, continues with many oligophosphoric acids such as diphosphoric acid...
). This bond involves combining a hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group from the inositol ring and a free phosphate group through a dehydration reaction
Dehydration reaction
In chemistry and the biological sciences, a dehydration reaction is usually defined as a chemical reaction that involves the loss of water from the reacting molecule. Dehydration reactions are a subset of elimination reactions...
. Considering that the average physiological pH is approximately 7.4, the main form of the phosphate groups bound to the inositol ring in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
is PO42-. This gives IP3 a net negative charge, which is important in allowing it to dock to its receptor, through binding of the phosphate groups to positively charged residues on the receptor. IP3 has three hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
donors in the form of its three hydroxyl groups. The hydroxyl group on the 6th carbon atom in the inositol ring is also involved in IP3 docking.
Binding of IP3 to its receptor
The docking of IP3 to its receptor, which is called the inositol trisphosphate receptor (Ins3PR), was first studied using deletion mutagenesisMutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
in the early 1990s.. Studies focused on the N-terminus side of the IP3 receptor. In 1997 researchers localized the region of the IP3 receptor involved with binding of IP3 to between amino acid
Amino 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...
residues 226 and 578 in 1997. Considering that IP3 is a negatively charged molecule, positively charged amino acids such as Arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
and Lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
, were believed to be involved. Two Arginine residues at position 265 and 511 and one Lysine residue at position 508 were found to be key in IP3 docking. Using a modified form of IP3, it was discovered that all three phosphate groups, phosphates at the 4th and 5th positions more extensively than the one at the 1st position, as well as the hydroxyl group at position 6 of the inositol ring interact with the receptor.
Discovery
The discovery that a horomone can influence phosphoinositide metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
was made by Mabel R. Hokin (1924-2003) and her then husband Lowell E. Hokin in 1953, when they discovered that radioactive 32P phosphate was incorporated into the phosphatidylinositol
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
of pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
slices when stimulated with acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
. Up until then phospholipids were believed to be innate structures only used by cells as building blocks for construction of the plasma membrane.
Over the next 20 years, little was discovered about the importance of PIP2 metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
in terms of cell signalling, until the mid-1970s when Robert H. Mitchell hypothesized a connection between the catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
of PIP2 and increases in intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
calcium
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...
(Ca2+ levels. He hypothesized that receptor-activated hydrolysis of PIP2 produced a molecule that caused increases in intracellular calcium mobilization. This idea was researched extensively by Mitchell and his colleagues, who in 1981 were able to show that PIP2 is hydrolyzed into DAG and IP3 by a then unknown phosphodiesterase
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
. In 1984 it was discovered that IP3 acts as a secondary messenger that is capable of traveling through the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
to 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...
(ER), where it stimulates the release of calcium into the cytoplasm.
Further research provided valuable information on the IP3 pathway, such as the discovery in 1986 that one of the many roles of the calcium released by IP3 is to work with DAG to activate 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). As well, it was discovered in 1989 that PLC is the phosphodiesterase responsible for hydrolyzing PIP2 into DAG and IP3. Today the IP3 signalling pathway is well mapped out and is known to be important in regulating a variety of calcium-dependent cell signalling pathways.
IP3 Signalling Pathway
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
binds to a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) that is coupled to a Gq heterotrimeric G protein, the α-subunit of Gq can bind to and induce activity in the PLC isozyme
Isozyme
Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...
PLC-β, which results in the cleavage of PIP2 into IP3 and DAG .
If a receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
(RTK) is involved in activating the pathway, the isozyme PLC-γ has [tyrosine] residues that can become phosphorylated upon activation of an RTK, and this will activate PLC-γ and allow it to cleave PIP2 into DAG and IP3. This occurs in cells that are capable of responding to growth factors such as insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, because the growth factors are the ligands responsible for activating the RTK.
IP3 is a soluble molecule and is capable of diffusing through the cytoplasm to the ER, or the sarcoplasmic reticulum (SR) in the case of muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells, once produced by PLC. Once at the ER, IP3 is able to bind to a the Ins3PR receptor on a ligand-gated Ca2+ channel that is found on the surface of the ER. The binding of IP3 to InsP3R triggers the opening of the Ca2+ channel and the release of Ca2+ into the cytoplasm . In muscle cells this increase in Ca2+ activates the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
-operated channel on the SR, results in further increases in Ca2+ through a process known as calcium-induced calcium release. IP3 may also activate Ca2+ channels on the cell membrane indirectly by increasing the intracellular Ca2+ concentration .
Human
Its main functions are to mobilize Ca2+ from storage organelleOrganelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
s and to regulate cell proliferation and other cellular reactions.
In smooth muscle cells, for example, the increase in concentration of cytoplasmic Ca2+ results in the contraction of the muscle cell.
In the nervous system, IP3 serves as a second messenger, with the 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...
containing the highest concentration of IP3 receptors. There is evidence that IP3 receptors play an important role in the induction of plasticity in cerebellar Purkinje cells.
Sea urchin eggs
The slow block to polyspermy in the sea urchin is mediated by the PIP2 secondary messenger system. Activation of the binding receptors activates PLC, which cleaves PIP2 in the egg plasma membrane, releasing IP3 into the egg cell cytoplasm. IP3 diffuses to the ER, where it opens Ca2+ channels.IP3 in Huntington's Disease
Huntington's diseaseHuntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
is an incurable genetic disorder
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that occurs when neurons in the brain
Brain
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,...
degenerate . Huntington’s disease primarily affects striatal medium spiny neurons (MSN). GABAergic MSNs make up more than 95% of all neurons in the striatum
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
. Huntington’s disease occurs when the cytosolic protein Huntingtin
Huntingtin
The Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
(Htt) has an additional 35 glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
residues added to its amino terminal region. This modified form of Htt is called Httexp. Httexp makes Type 1 IP3 receptors more sensitive to IP3, which leads to the release of too much Ca2+ from the ER. The release of Ca2+ from the ER causes an increase in the cytosolic and mitochondrial concentrations of Ca2+. This increase in Ca2+ is thought to be the cause of GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
ergic MSN degradation
IP3 in Alzheimer’s Disease
Alzheimer’s disease is a disease in which progressive degeneration of the brain occurs, severely impacting one’s mental faculties . Since the Ca2+ hypothesis of Alzheimer’s was proposed in 1994, several studies have shown that disruptions in Ca2+ signalling are the primary cause of Alzheimer’s disease. Familial Alzheimer’s disease has been strongly linked to mutations in the presenilin 1 (PS1), presenilin 2 (PS2), and amyloid precursor proteinAmyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(APP) genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
. All of the mutated forms of these genes observed to date have been found to cause abnormal Ca2+ signaling in the ER. The functions of PS1 are not yet known, but mutations in PS1 have been shown to increase IP3-mediated Ca2+ release from the ER in several animal models. Calcium channel blockers have been used to treat Alzheimer’s disease with some success, and the use of lithium to decrease IP3 turnover has also been suggested as a possible method of treatment .
See also
- inositolInositolInositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
- inositol phosphateInositol phosphateInositol phosphates are a group of mono- to polyphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.The group comprises:...
- myo-inositol
- inositol pentakisphosphateInositol pentakisphosphateInositol pentakisphosphate is a molecule derived from inositol tetrakisphosphate by adding a phosphate group with the help of inositol polyphosphate multikinase . It is believed to be one of the many second messengers in the inositol phosphate family...
- inositol hexaphosphate
- inositol triphosphate receptorInositol triphosphate receptorInositol trisphosphate receptor is a membrane glycoprotein complex acting as Ca2+ channel activated by inositol trisphosphate . InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiological processes including cell division, cell proliferation, apoptosis,...
- ITPR1ITPR1Inositol 1,4,5-trisphosphate receptor type 1 is a protein that in humans is encoded by the ITPR1 gene.-Interactions:ITPR1 has been shown to interact with CA8, PRKG1, FKBP1A, MRVI1, RHOA, AHCYL1, EPB41L1 and TRPC4.-External Links:*...
- ITPKCITPKCITPKC is a gene that has been associated with Kawasaki disease.It codes an enzyme that negatively regulates T-cell activation....