Dendrin

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Dendrin is a neural and renal protein whose exact function is still relatively unclear; however, its location in the brain and kidneys is well known as are some of the neural processes it affects. Within the brain, dendrin can be found in neurons and is most notably associated with sleep deprivation. Sleep deprivation causes some areas of the brain dendrin levels to increase, but this increase is insignificant and in total sleep deprivation causes a decrease of the mRNA and protein form of dendrin. [1] Along with two other proteins, MAGI/S-SCAM and α-actinin, dendrin is linked to synaptic plasticity and memory formation in the brain. [2] Nicotine levels have also been shown to have an effect on dendrin expression in the brain. Although unlike sleep deprivation, nicotine increases overall dendrin level. [3] Originally thought to be a brain specific protein, there is now evidence to suggest that dendrin is also found in the kidneys. [4] Dendrin is used to detect glomerulopathy or renal disease, based on its location in the kidneys. [5] Within the kidneys it also works to prevent urinary protein loss. [6] Most studies and information on dendrin pertain specifically to rat or mice brains.

Contents

Structure

Dendrin has a similar structure in mice, rats, and humans. [6] The protein is composed of 2,067 nucleotides, is hydrophilic, and is rich in the animo acid proline. Dendrin is a protein kinase substrate that is composed of multiple consensus sites for phosphorylation by protein kinase C, casein kinase 11, CAMP-dependent and proline-dependent kinases, and tyrosine kinase. Surprisingly, the protein structure does not have any secondary structure patterns, such as lengthy regions of α helices or β sheets. [1] Appropriately named, dendrin in its mRNA form is often found in the dendrites of neurons. [3] The unique structure of dendrin allows it to participate in many different processes, such as synaptic plasticity in the brain and disease detection in the kidneys.

Discovery

Dendrin was originally discovered in rat neurons and encoded by the brain specific transcript 464 by M. Neuner-Jehle. In 1996, 6 rats were tested using affinity-purified polyclonal rabbit anti-dendrin antibodies. Using this technique two different proteins were identified one of which was dendrin. Dendrin expression was measured in sleep deprived rats and in control rats. Neuner-Jehle found that when the rats were sleep deprived, dendrin levels decreased. Neuner-Jehle also studied the location of dendrin expression by staining brain sections and was able to show the areas that were richest with dendrin. Most notably, the greatest protein was found in the forebrain and hippocampus. After this initial study, it was assumed that dendrin was located only in the brain. [1] However, in 2006, Kawata et al. found that the dendrin protein is also located in the kidneys. A yeast two-hybrid screening of kidney cDNA proved to find dendrin in the kidney podocytes, where it connects to cytoskeleton proteins: S-S-SCAM and CIN85. [4]

Location

Dendrin is expressed in the forebrain (pictured in red above and in the hippocampus of the brain EmbryonicBrain.svg
Dendrin is expressed in the forebrain (pictured in red above and in the hippocampus of the brain

It is now known that dendrin is found in the brain and kidneys, but it is not expressed everywhere in these two organs. Dendrin has only been found in a very specific part of the brain and specific parts of the kidneys. Within the brain, dendrin is normally found in the forebrain and hippocampus and in the kidneys, dendrin is normally found in the slit diaphragm and podocytes. It is believed that the location of this protein may directly affect its function, both in the brain and in the kidneys.

Brain

Dendrin is a postsynaptic protein [4] that is found in the forebrain and hippocampus. Specifically in the forebrain, dendrin is found in the cerebral cortex and the subcortical forebrain plus midbrain areas (SFMA). [1] Dendrin has yet to be found in other parts of the brain, but is very abundant in the parts of the brain where it is known to be expressed. Within these known locations in the brain, dendrin is associated with the actin cytoskeleton. [7] Dendrin is found in the neuron's cell body and its dendrites. [8] This is the part of the cell that helps it to retain its structure and move other molecules throughout the cell. MAGI/S-SCAM is a component of the cytoskeleton that is used to keep dendrin in the cytoplasm of a neuron, and prevents the protein from diffusing into the nucleus. Because of this location in the neuron, it is thought that dendrin is involved in retrograde signaling from the synapse to the nucleus. [2] This form of signaling is the reverse of normal neural signaling so that instead of the signal passing from the nucleus to the synapse, is passes from the synapse to the nucleus.

Kidneys

Renal corpuscle showing the podocytes, where dendrin is located in the kidneys Renal corpuscle-en.svg
Renal corpuscle showing the podocytes, where dendrin is located in the kidneys

Dendrin is also expressed during mouse glomerulogenesis. The protein is usually expressed during the early capillary loop stage of glomerulogenesis and creates a linear pattern on the epithelial side of these loops. In normal mature kidneys, dendrin is found only in the podocytes near the slit diaphragm. [7] Podocytes are epithelia cells in the kidneys that do not readily divide and act as a barrier that prevent urinary protein loss. [5] [6] Dendrin interacts with S-SCAM (used in organization of synapses) and CIN85, two scaffold proteins in the kidneys. Within this organ, dendrin's functions include the prevention of urinary protein loss and the formation of protein-protein interaction webs at dendritic spines. [6] [4]

Slit Diaphragm

The slit diaphragm is a part of the kidneys that regulates renal ultrafiltration. [9] Specifically, it is a part of the glomerular filter, which separates blood from urine. The slit diaphragm is very thin molecular sheet that mainly filters out plasma proteins and separates the foot processes of glomerular podocytes. [10] The slit diaphragm is attached to the actin cytoskeleton of the cell. Dendrin associates regularly with the slit diaphragm because the dendrin protein is located in these podocytes. [7] [10]

Function

Although the exact function of dendrin is not known, there is a great deal of data to show what processes it contributes to and potentially regulates. Dendrin is normally affected by different behaviors. Most commonly studied in rats, dendrin is known to decrease with prolonged sleep deprivation and increase with acute nicotine intake. Within the brain, dendrin interacts with α-actinin in postsynaptic dendritic spines. [7] Together MAGI/S-SCAM, α-actinin, and dendrin form a tertiary complex at postsynaptic neural sites. This trio of proteins helps to connect a dense filamentous lattice (postsynaptic density or PSD) to the cytoskeleton of the spine and is also linked to synaptic plasticity and memory formation. [2] Additionally, the protein binds to nephrin and CD2AP within the kidneys, where can help with intracellular signaling pathways. In conjunction with the slit diaphragm, dendrin helps to prevent urinary protein loss. [6]

Sleep Deprivation's Effect on Dendrin

When dendrin was originally discovered, it was associated with sleep deprivation. Lack of sleep causes a decrease in dendrin mRNA concentrations even after only 24 hours of no sleep. There is a slight increase in dendrin mRNA in the hippocampus caused by sleep deprivation although it is very minimal. Within the cerebral cortex, dendrin mRNA concentrations remain unchanged. Even though some dendrin levels in the brain rise or remain unchanged when sleep deprivation occurs, overall the levels of dendrin decrease. Through multiple studies it was found that there is a correlation between the levels of dendrin and sleep deprivation. [1] Since it is still not clear what role dendrin plays in the brain, it is unclear how the processes dendrin is involved in are affected by lack of sleep.

Nicotine's effect on dendrin

Even a small amount of nicotine (pictured above) can have an effect on dendrin levels. Nicotine.svg
Even a small amount of nicotine (pictured above) can have an effect on dendrin levels.

Dendrin mRNA levels are increased with nicotine use in adolescent rat brains; however, these same levels of protein do not change in adults rats. It has also been shown that dendrin expression is not altered by cocaine or by placing the subject in a new or different environment. The proteins that dendrin typically associates with tend to be proteins that are linked to synaptic modification and learning. Expression of dendrin with even a small amount of nicotine could alter these processes and functions. Increased expression of dendrin caused by nicotine use is found mostly in the forebrain region of rats. Additional increase in dendrin mRNA is also found in the striatum. [3]

Synaptic Plasticity

The protein trio of MAGI/S-SCAM, α-actinin, and dendrin helps to connect postsynaptic density (PSD) to the cytoskeleton of the spine. The spatially restricted synthesis of dendrin contributes to the regulation of the synaptic cytoskeleton. The postsynaptic cytoskeleton, in turn, is involved in synaptic plasticity and memory formation suggesting that dendrin expression plays a role in these two brain functions. [2] If the synapse is damaged, this protein trio may play a role in its ability to regain function or the synaptic function to be taken over by another part of the brain. The involvement of dendrin in memory formation also suggests that external influences like sleep deprivation or nicotine consumption can alter or affect how memories are formed or stored.

Regulation of Dendrin

Down-regulation of dendrin is due to sleep deprivation which reduces the numbers of dendrin in the neuron. [1] Sleep deprivation causes the most notable regulation and while it does not cause a decrease in dendrin mRNA and protein everywhere in the brain, the most significant change in dendrin levels is an overall decrease. Dendrin is regulated in the kidneys by CD2AP, which assists in dendrin movement to the nucleus of the podocyte. This movement mainly occurs when an injury, or cell death occurs in the podocyte epithelial cells. [10]

Injury in the Kidneys

When there is glomerular injury in the kidneys, the dendrin protein relocates to the podocyte nucleus in the slit diaphragm. The movement of this protein to the podocyte is associated with podocyte apoptosis. There is proof that the action of a podocyte cell killing itself causes dendrin to move to the nucleus. Damage to the podocytes causes the silt diaphragm to collapse and tight junctions, or cell to cell connections to be formed. It has been shown that dendrin is involved in promoting apoptosis of the podocytes. [10] Apoptosis leads to a decrease in podocyte epithelial cells which causes proteinuria and could culminate in glomerulosclerosis. This relocation of dendrin can potentially help to diagnose any kidney damage or kidney disease. Dendrin locations in the kidneys can help determine the stage of glomerulosclerosis and how many podocytes have been lost to apoptosis. [5]

Related Research Articles

<span class="mw-page-title-main">Neuron</span> Electrically excitable cell found in the nervous system of animals

A neuron, neurone, or nerve cell is an excitable cell that fires electric signals called action potentials across a neural network in the nervous system. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Dendritic spine</span> Small protrusion on a dendrite that receives input from a single axon

A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. Most spines have a bulbous head, and a thin neck that connects the head of the spine to the shaft of the dendrite. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons. It has also been suggested that changes in the activity of neurons have a positive effect on spine morphology.

<span class="mw-page-title-main">Long-term potentiation</span> Persistent strengthening of synapses based on recent patterns of activity

In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons. The opposite of LTP is long-term depression, which produces a long-lasting decrease in synaptic strength.

<span class="mw-page-title-main">Synaptic plasticity</span> Ability of a synapse to strengthen or weaken over time according to its activity

In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell-to-cell signalling. EPSPs and IPSPs compete with each other at numerous synapses of a neuron. This determines whether an action potential occurring at the presynaptic terminal produces an action potential at the postsynaptic membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

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<span class="mw-page-title-main">Podocyte</span> Type of kidney cell

Podocytes are cells in Bowman's capsule in the kidneys that wrap around capillaries of the glomerulus. Podocytes make up the epithelial lining of Bowman's capsule, the third layer through which filtration of blood takes place. Bowman's capsule filters the blood, retaining large molecules such as proteins while smaller molecules such as water, salts, and sugars are filtered as the first step in the formation of urine. Although various viscera have epithelial layers, the name visceral epithelial cells usually refers specifically to podocytes, which are specialized epithelial cells that reside in the visceral layer of the capsule.

Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.

<span class="mw-page-title-main">Postsynaptic density</span>

The postsynaptic density (PSD) is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron. The PSD is in close apposition to the presynaptic active zone and ensures that receptors are in close proximity to presynaptic neurotransmitter release sites. PSDs vary in size and composition among brain regions, and have been studied in great detail at glutamatergic synapses. Hundreds of proteins have been identified in the postsynaptic density, including glutamate receptors, scaffold proteins, and many signaling molecules.

Metaplasticity is a term originally coined by W.C. Abraham and M.F. Bear to refer to the plasticity of synaptic plasticity. Until that time synaptic plasticity had referred to the plastic nature of individual synapses. However this new form referred to the plasticity of the plasticity itself, thus the term meta-plasticity. The idea is that the synapse's previous history of activity determines its current plasticity. This may play a role in some of the underlying mechanisms thought to be important in memory and learning such as long-term potentiation (LTP), long-term depression (LTD) and so forth. These mechanisms depend on current synaptic "state", as set by ongoing extrinsic influences such as the level of synaptic inhibition, the activity of modulatory afferents such as catecholamines, and the pool of hormones affecting the synapses under study. Recently, it has become clear that the prior history of synaptic activity is an additional variable that influences the synaptic state, and thereby the degree, of LTP or LTD produced by a given experimental protocol. In a sense, then, synaptic plasticity is governed by an activity-dependent plasticity of the synaptic state; such plasticity of synaptic plasticity has been termed metaplasticity. There is little known about metaplasticity, and there is much research currently underway on the subject, despite its difficulty of study, because of its theoretical importance in brain and cognitive science. Most research of this type is done via cultured hippocampus cells or hippocampal slices.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

<span class="mw-page-title-main">Neuroligin</span> Protein

Neuroligin (NLGN), a type I membrane protein, is a cell adhesion protein on the postsynaptic membrane that mediates the formation and maintenance of synapses between neurons. Neuroligins act as ligands for β-neurexins, which are cell adhesion proteins located presynaptically. Neuroligin and β-neurexin "shake hands", resulting in the connection between two neurons and the production of a synapse. Neuroligins also affect the properties of neural networks by specifying synaptic functions, and they mediate signalling by recruiting and stabilizing key synaptic components. Neuroligins interact with other postsynaptic proteins to localize neurotransmitter receptors and channels in the postsynaptic density as the cell matures. Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis. In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders. Antibodies in a mother from previous male pregnancies against neuroligin 4 from the Y chromosome increase the probability of homosexuality in male offspring.

<span class="mw-page-title-main">Nonsynaptic plasticity</span> Form of neuroplasticity

Nonsynaptic plasticity is a form of neuroplasticity that involves modification of ion channel function in the axon, dendrites, and cell body that results in specific changes in the integration of excitatory postsynaptic potentials and inhibitory postsynaptic potentials. Nonsynaptic plasticity is a modification of the intrinsic excitability of the neuron. It interacts with synaptic plasticity, but it is considered a separate entity from synaptic plasticity. Intrinsic modification of the electrical properties of neurons plays a role in many aspects of plasticity from homeostatic plasticity to learning and memory itself. Nonsynaptic plasticity affects synaptic integration, subthreshold propagation, spike generation, and other fundamental mechanisms of neurons at the cellular level. These individual neuronal alterations can result in changes in higher brain function, especially learning and memory. However, as an emerging field in neuroscience, much of the knowledge about nonsynaptic plasticity is uncertain and still requires further investigation to better define its role in brain function and behavior.

<span class="mw-page-title-main">Activity-regulated cytoskeleton-associated protein</span> Protein-coding gene in the species Homo sapiens

Activity-regulated cytoskeleton-associated protein is a plasticity protein that in humans is encoded by the ARC gene. The gene is believed to derive from a retrotransposon. The protein is found in the neurons of tetrapods and other animals where it can form virus-like capsids that transport RNA between neurons.

Synaptic tagging, or the synaptic tagging hypothesis, has been proposed to explain how neural signaling at a particular synapse creates a target for subsequent plasticity-related product (PRP) trafficking essential for sustained LTP and LTD. Although the molecular identity of the tags remains unknown, it has been established that they form as a result of high or low frequency stimulation, interact with incoming PRPs, and have a limited lifespan.

Actin remodeling is a biochemical process in cells. In the actin remodeling of neurons, the protein actin is part of the process to change the shape and structure of dendritic spines. G-actin is the monomer form of actin, and is uniformly distributed throughout the axon and the dendrite. F-actin is the polymer form of actin, and its presence in dendritic spines is associated with their change in shape and structure. Actin plays a role in the formation of new spines as well as stabilizing spine volume increase. The changes that actin brings about lead to the formation of new synapses as well as increased cell communication.

<span class="mw-page-title-main">Synaptic stabilization</span> Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

An axo-axonic synapse is a type of synapse, formed by one neuron projecting its axon terminals onto another neuron's axon.

References

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