Activity-regulated cytoskeleton-associated protein is a
plasticity
Plasticity may refer to:
Science
* Plasticity (physics), in engineering and physics, the propensity of a solid material to undergo permanent deformation under load
* Neuroplasticity, in neuroscience, how entire brain structures, and the brain it ...
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''ARC''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. It was first characterized in 1995.
''ARC'' is a member of the
immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be
transcribed in the presence of
protein synthesis inhibitor
A protein synthesis inhibitor is a compound that stops or slows the growth or proliferation of cells by disrupting the processes that lead directly to the generation of new proteins.
While a broad interpretation of this definition could be used t ...
s. ''ARC''
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
is localized to activated synaptic sites in an
NMDA receptor
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA rece ...
-dependent manner,
where the newly
translated
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. The English language draws a terminological distinction (which does not exist in every language) between ''transla ...
protein is believed to play a critical role in learning and memory-related molecular processes.
Arc protein is widely considered to be important in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunction in the production of Arc protein has been implicated as an important factor in understanding various neurological conditions, including
amnesia
Amnesia is a deficit in memory caused by brain damage or disease,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be caused temporarily by the use ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
,
Autism spectrum disorders
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
, and
Fragile X syndrome
Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...
. Along with other IEGs such as ''
ZNF268'' and ''
HOMER1
Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the ''HOMER1'' gene. Other names are Vesl and PSD-Zip45.
Structure
Homer1 protein has an N-terminal EVH1 domain, involved in protein interaction, and a C-te ...
'', ''ARC'' is also a significant tool for
systems neuroscience as illustrated by the development of the ''cellular compartment analysis of temporal activity by fluorescence in situ hybridization'', or catFISH technique
(see
fluorescent in situ hybridization
Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed ...
).
Gene
The ''ARC'' gene, located on
chromosome
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
15 in the
mouse
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
, chromosome 7 in the
rat, and chromosome 8 in the
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
, is conserved across vertebrate species and has low sequence homology to spectrin,
a cytoskeletal protein involved in forming the
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
cellular cortex. A number of
promoter and
enhancer regions have been identified that mediate activity-dependent Arc transcription: a serum response element (SRE; see
serum response factor
Serum response factor, also known as SRF, is a transcription factor protein.
Function
Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
) at ~1.5 kb upstream of the initiation site.
a second SRE at ~6.5 kb;
and a synaptic activity response element (SARE) sequence at ~7 kb upstream that contains binding sites for
cyclic AMP response element-binding protein (CREB),
myocyte enhancer factor 2 (MEF2), and SRF.
The
3' UTR of the mRNA contains a
cis-acting
''Cis''-regulatory elements (CREs) or ''Cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morpho ...
element required for the localization of Arc to neuronal dendrites,
as well as sites for two
exon junction complex
An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance and local ...
es (EJCs)
that make Arc a natural target for
nonsense mediated decay
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...
(NMD).
Also important for translocation of cytoplasmic Arc mRNA to activated synapses is an 11 nucleotide binding site for
heterogeneous nuclear ribonucleoprotein Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the pr ...
A2 (hnRNP A2).
It is suspected that Arc gene originated from Ty3/gypsy retrotransposons and was repurposed for mediating neuron-neuron communication.
Protein
Once transported, the translated protein is 396 residues in length, with an
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
located at amino acids 1-25, a
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
at 155-396 (note that the spectrin homology located at 228-380 within the C-terminal), and a putative
coiled coil
A coiled coil is a structural motif in proteins in which 2–7
alpha-helices are coiled together like the strands of a rope. (Dimers and trimers are the most common types.) Many coiled coil-type proteins are involved in important biological fun ...
domain at amino acids 26-154.
Additionally, the protein has binding sites for endophilin 3 and dynamin 2 at amino acids 89-100 and 195-214, respectively.
While Arc mRNA is subject to degradation by NMD, the translated protein contains a
PEST sequence
A PEST sequence is a peptide sequence that is rich in proline (P), glutamic acid (E), serine (S), and threonine (T). This sequence is associated with proteins that have a short intracellular half-life; therefore, it is hypothesized that the PES ...
at amino acids 351-392, indicating
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
-dependent degradation.
The translated protein can be visualized with an
immunoblot
The western blot (sometimes called the protein immunoblot), or western blotting, is a widely used analytical technique in molecular biology and immunogenetics to detect specific proteins in a sample of tissue homogenate or extract. Besides detect ...
as a band at 55 kDa. The ARC protein can form virus-like
capsids
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...
that package mRNA and can traffic between cells.
Trafficking
Following transcription, Arc mRNA is transported out of the nucleus and localized to neuronal dendrites
and activated synapses,
a process dependent on the 3' UTR,
polymerization of
actin
Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
,
and
ERK phosphorylation.
The mRNA (and aggregate protein) is carried along
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
s radiating out from the nucleus by
kinesin
A kinesin is a protein belonging to a class of motor proteins found in eukaryotic cells.
Kinesins move along microtubule (MT) filaments and are powered by the hydrolysis of adenosine triphosphate (ATP) (thus kinesins are ATPases, a type of enzy ...
(specifically KIF5)
and likely translocated into
dendritic spine
A dendritic spine (or 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 si ...
s by the actin-based motor protein
myosin
Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility.
The first myosin ...
-Va.
Arc has been shown to be associated with
polyribosome
A polyribosome (or polysome or ergosome) is a group of ribosomes bound to an mRNA molecule like “beads” on a “thread”. It consists of a complex of an mRNA molecule and two or more ribosomes that act to translate mRNA instructions into pol ...
s at synaptic sites,
and is translated in isolated synaptoneurosomal fractions
''in vitro'' indicating that the protein is likely locally translated ''in vivo''.
Synaptically localized Arc protein interacts with
dynamin
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily
Dynamin Superfamily Protein (DSP) is a protein superfamily includes classical dynamins, GBPs, Mx proteins, OPA1, mitofusins i ...
and endophilin, proteins involved in
clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1976. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. Whe ...
-mediated
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
, and facilitates the removal of AMPA receptors from the plasma membrane.
Consistent with this, increased Arc levels reduce AMPA currents,
while Arc KOs display increases in surface AMPA expression.
Knockouts
Arc is critical as a ubiquitous signaling factor in early embryonic development and is required for growth and patterning during
gastrulation
Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...
.
The first
knockouts (KOs) for Arc were therefore incompatible with life. Subsequent efforts produced
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
knockout mice by targeting the entire Arc gene rather than portions of the coding region, eliminating
dominant negative
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
effects. These animals proved viable and exhibit no gross malformations in neuronal architecture, but express higher levels of the
GluR1 subunit and increased miniature
excitatory postsynaptic currents (mEPSCs) in addition to displaying deficiencies in
long-term memory
Long-term memory (LTM) is the stage of the Atkinson–Shiffrin memory model in which informative knowledge is held indefinitely. It is defined in contrast to short-term and working memory, which persist for only about 18 to 30 seconds. Long-t ...
.
Signaling
The Arc transcript is dependent upon activation of the
mitogen-activated protein kinase
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
or MAP kinase (MAPK) cascade,
a pathway important for regulation of cell growth and survival.
Extracellular signaling to neuronal dendrites activates postsynaptic sites to increase Arc levels through a wide variety of signaling molecules, including mitogens such as
epidermal growth factor
Epidermal growth factor (EGF) is a protein that stimulates cell growth and differentiation by binding to its receptor, EGFR. Human EGF is 6-k Da and has 53 amino acid residues and three intramolecular disulfide bonds.
EGF was originally descr ...
(EGF),
nerve growth factor
Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was on ...
(NGF),
and
brain-derived neurotrophic factor
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
(BDNF),
glutamate acting at NMDA receptors,
dopamine through activation of the
D1 receptor subtype,
and
dihydroxyphenylglycine
(''S'')-3,5-Dihydroxyphenylglycine or DHPG is a potent agonist of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5.
DHPG was the first agonist shown to be selective for group I mGluRs. Agonist activity is found in only the ( ...
(DHPG).
The common factor for these signaling molecules involves activation of
cyclic-AMP and its downstream target
protein kinase A
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(PKA). As such, direct pharmacological activation of cAMP by forskolin or 8-Br-cAMP robustly increases Arc levels
while H89, a PKA antagonist, blocks these effects
as does further downstream blockade of
mitogen-activated protein kinase kinase
Mitogen-activated protein kinase kinase (also known as MAP2K, MEK, MAPKK) is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).
MAP2K is classified as .
There are seven genes:
* (a.k.a. MEK1)
* ( ...
ic(MEK).
Note that the MAPK cascade is a signaling pathway involving multiple
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
s acting sequentially
MAPKK--> MAPK">APKKK--> MAPKK--> MAPK
MAPK is able to enter the nucleus and perform its phosphotransferase activity on a number of gene regulatory components
that have implications for the regulation of immediate-early genes. Several
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
s are known to be involved in regulating the Arc gene (see above), including
serum response factor
Serum response factor, also known as SRF, is a transcription factor protein.
Function
Serum response factor is a member of the MADS (MCM1, Agamous, Deficiens, and SRF) box superfamily of transcription factors. This protein binds to the serum ...
(SRF),
CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
,
MEF2
In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical rol ...
,
and
zif268
EGR-1 (Early growth response protein 1) also known as ZNF268 (zinc finger protein 268) or NGFI-A (nerve growth factor-induced protein A) is a protein that in humans is encoded by the ''EGR1'' gene.
EGR-1 is a mammalian transcription factor. It wa ...
.
Behavioral effects
Changes in Arc mRNA and/or protein are correlated with a number of behavioral changes including cued
fear conditioning
Pavlovian fear conditioning is a behavioral paradigm in which organisms learn to predict aversive events. It is a form of learning in which an aversive stimulus (e.g. an electrical shock) is associated with a particular neutral context (e.g., a r ...
,
contextual fear conditioning,
spatial memory,
operant conditioning
Operant conditioning, also called instrumental conditioning, is a learning process where behaviors are modified through the association of stimuli with reinforcement or punishment. In it, operants—behaviors that affect one's environment—are c ...
,
and inhibitory avoidance.
The mRNA is notably upregulated following electrical stimulation in
LTP-induction procedures such as high frequency stimulation (HFS),
and is massively and globally induced by maximal electroconvulsive shock (MECS).
Arc in insects
Meanwhile it has been found that Arc may have been acquired by animals more than once. While Arc seems to be closely related among all
tetrapods
Tetrapods (; ) are four-limbed vertebrate animals constituting the superclass Tetrapoda (). It includes extant and extinct amphibians, sauropsids (reptiles, including dinosaurs and therefore birds) and synapsids (pelycosaurs, extinct therapsids ...
, the one which has been found in
fruit flies
Fruit fly may refer to:
Organisms
* Drosophilidae, a family of small flies, including:
** ''Drosophila'', the genus of small fruit flies and vinegar flies
** ''Drosophila melanogaster'' or common fruit fly
** ''Drosophila suzukii'' or Asian fruit ...
(''Drosophila melanogaster''),
silkworms
The domestic silk moth (''Bombyx mori''), is an insect from the moth family Bombycidae. It is the closest relative of ''Bombyx mandarina'', the wild silk moth. The silkworm is the larva or caterpillar of a silk moth. It is an economically imp ...
(''Bombyx mori''), and
Argentine ant
The Argentine ant (''Linepithema humile''), formerly ''Iridomyrmex humilis'', is an ant native to northern Argentina, Uruguay, Paraguay, Bolivia and southern Brazil. It is an invasive species that has been established in many Mediterranean c ...
s (''Linepithema humile'') may have been transferred to a common ancestor of these insects by another event.
References
External links
*
{{DEFAULTSORT:Arc (Protein)
Proteins
Molecular biology