Neurexin

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Neurexin family
Identifiers
SymbolNRXN1_fam
Membranome 15
neurexin 1
3D ribbon diagram of alpha-neurexin 1.png
3D ribbon diagram of alpha-neurexin 1
Identifiers
Symbol NRXN1
NCBI gene 9378
HGNC 8008
OMIM 600565
RefSeq NM_001135659.1
UniProt Q9ULB1
Other data
Locus Chr. 2 p16.3
Search for
Structures Swiss-model
Domains InterPro
neurexin 2
Identifiers
Symbol NRXN2
NCBI gene 9379
HGNC 8009
OMIM 600566
RefSeq NM_015080
UniProt P58401
Other data
Locus Chr. 11 q13.1
Search for
Structures Swiss-model
Domains InterPro
neurexin 3
Identifiers
Symbol NRXN3
NCBI gene 9369
HGNC 8010
OMIM 600567
RefSeq NM_001105250
UniProt Q9HDB5
Other data
Locus Chr. 14 q31
Search for
Structures Swiss-model
Domains InterPro
neurexin
Identifiers
Organism Drosophila melanogaster
SymbolNrx-IV
Entrez 39387
RefSeq (mRNA) NM_168491.3
RefSeq (Prot) NP_524034.2
UniProt Q94887
Other data
Chromosome 3L: 12.14 - 12.15 Mb
Search for
Structures Swiss-model
Domains InterPro
neurexin
Identifiers
Organism Mus musculus
SymbolNrxn1
Entrez 18189
RefSeq (mRNA) NM_177284.2
RefSeq (Prot) NP_064648.3
UniProt Q9CS84
Other data
Chromosome 17: 90.03 - 91.09 Mb
Search for
Structures Swiss-model
Domains InterPro

Neurexins (NRXN) are a family of presynaptic cell adhesion proteins that have roles in connecting neurons at the synapse. [1] They are located mostly on the presynaptic membrane and contain a single transmembrane domain. The extracellular domain interacts with proteins in the synaptic cleft, most notably neuroligin, while the intracellular cytoplasmic portion interacts with proteins associated with exocytosis. [2] Neurexin and neuroligin "shake hands," resulting in the connection between the two neurons and the production of a synapse. [3] Neurexins mediate signaling across the synapse, and influence the properties of neural networks by synapse specificity. [4] Neurexins were discovered as receptors for α-latrotoxin, a vertebrate-specific toxin in black widow spider venom that binds to presynaptic receptors and induces massive neurotransmitter release. [5] In humans, alterations in genes encoding neurexins are implicated in autism and other cognitive diseases, such as Tourette syndrome and schizophrenia. [5]

Contents

Structure

In mammals, neurexin is encoded by three different genes (NRXN1, NRXN2, and NRXN3) each controlled by two different promoters, an upstream alpha (α) and a downstream beta (β), resulting in alpha-neurexins 1-3 (α-neurexins 1–3) and beta-neurexins 1-3 (β-neurexins 1–3). [6] In addition, there are alternative splicing at 5 sites in α-neurexin and 2 in β-neurexin; more than 2000 splice variants are possible, suggesting its role in determining synapse specificity. [7]

The encoded proteins are structurally similar to laminin, slit, and agrin, other proteins involved in axon guidance and synaptogenesis. [7] α-Neurexins and β-neurexins have identical intracellular domains but different extracellular domains. The extracellular domain of α-neurexin is composed of three neurexin repeats which each contain LNS (laminin, neurexin, sex-hormone binding globulin) – EGF (epidermal growth factor) – LNS domains. N1α binds to a variety of ligands including neuroligins and GABA receptors, [2] though neurons of every receptor type express neurexins. β-Neurexins are shorter versions of α-neurexins, containing only one LNS domain. [8] β-Neurexins (located presynaptically) act as receptors for neuroligin (located postsynaptically). Additionally, β-Neurexin has also been found to play a role in angiogenesis. [9]

The C terminus of the short intracellular section of both types of neurexins binds to synaptotagmin and to the PDZ (postsynaptic density (PSD)-95/discs large/zona-occludens-1) domains of CASK and Mint. These interactions form connections between intracellular synaptic vesicles and fusion proteins. [10] Thus neurexins play an important role in assembling presynaptic and postsynaptic machinery.

Trans-synapse, the extracellular LNS domains have a functional region, the hyper-variable surface, formed by loops carrying 3 splice inserts. [2] This region surrounds a coordinated Ca2+ ion and is the site of neuroligin binding, [10] resulting in a neurexin-neuroligin Ca2+-dependent complex at the junction of chemical synapses. [11]

Expression and function

Neurexins are diffusely distributed in neurons and become concentrated at presynaptic terminals as neurons mature. They have also been found at pancreatic beta islet cells even though the function at this location has yet to be elucidated. [4] There exists a trans-synaptic dialog between neurexin and neuroligin. [12] This bi-directional trigger aids in the formation of synapses and is a key component to modifying the neuronal network. Over-expression of either of these proteins causes an increase in synapse forming sites, thus providing evidence that neurexin plays a functional role in synaptogenesis. [8] Conversely, the blocking of β-neurexin interactions reduces the number of excitatory and inhibitory synapses. It is not clear how exactly neurexin promotes the formation of synapses. One possibility is that actin is polymerized on the tail end of β-neurexin, which traps and stabilizes accumulating synaptic vesicles. This forms a forward feeding cycle, where small clusters of β-neurexins recruit more β-neurexins and scaffolding proteins to form a large synaptic adhesive contact. [8]

Neurexin Binding Partners

Neurexin-Neureoligin binding

The trans-synaptic dialog between neurexin and neuroligin organizes the apposition of pre- and post-synaptic machinery by recruiting scaffolding proteins and other synaptic elements such as NMDA receptors, CASK, and synaptotagmin, all of which are necessary for a synapse to exist. Cartoon of neurexin and neurolign interaction.png
The trans-synaptic dialog between neurexin and neuroligin organizes the apposition of pre- and post-synaptic machinery by recruiting scaffolding proteins and other synaptic elements such as NMDA receptors, CASK, and synaptotagmin, all of which are necessary for a synapse to exist.

The different combinations of neurexin to neuroligin, and alternative splicing of neuroligin and neurexin genes, control binding between neuroligins and neurexins, adding to synapse specificity. [8] Neurexins alone are capable of recruiting neuroligins in postsynaptic cells to a dendritic surface, resulting in clustered neurotransmitter receptors and other postsynaptic proteins and machinery. Their neuroligin partners can induce presynaptic terminals by recruiting neurexins. Synapse formation can therefore be triggered in either direction by these proteins. [10] Neuroligins and neurexins can also regulate formation of glutamatergic (excitatory) synapses, and GABAergic (inhibitory) contacts using a neuroligin link. Regulating these contacts suggests neurexin-neuroligin binding could balance synaptic input, [7] or maintain an optimal ratio of excitatory to inhibitory contacts.

Additional interacting partners

Dystroglycans

Neurexins not only bind to neuroligin. Additional binding partners of neurexin are dystroglycan. [10] Dystroglycan is Ca2+-dependent and binds preferentially to α-neurexins on LNS domains that lack splice inserts. In mice, a deletion of dystroglycan causes long-term potentiation impairment and developmental abnormalities similar to muscular dystrophy; however baseline synaptic transmission is normal.

Neuroexophilins

Representation of Neurexin and binding partners in the synaptic cleft Neurexinbinding.jpeg
Representation of Neurexin and binding partners in the synaptic cleft

Neuroexophilins are also known to bind to neurexins and are present at the synaptic cleft but are not membrane bound. [10] [13] Neuroexophilins are Ca2+-independent and bind exclusively to α-neurexins on the second LNS domain. The increased startle responses and impaired motor coordination of neuroexophilin knockout mice indicates that neuroexophilins have a functional role in certain circuits. [10]

Latrophilins

Latrophilins are adhesion G protein-coupled receptors that reside on the postsynaptic membrane. [13] Without latrophillins in mice a loss of excitatory synapses was experienced in pyramidal neurons. [14] Latrophillins while in association with neurexin have been shown to act as postsynaptic recognition molecules for incoming axons. [13]

Cerebellins

Cerebellins are small proteins that are secreted into the synaptic cleft where they associate with other cerebellins to form a hexamer which binds two neurexins. [15] Cerebellins bind to GluD1 and GluD2 on the postsynaptic side while bound to neurexin presynaptically. GluD1 and GluD2 are homologous to ionotropic glutamate receptors, but function as adhesion molecules instead of glutamate receptors. [13] Despite being present throughout the brain, their function is only known within the cerebellum, the structure they are named after. When removed from the cerebellum a decrease of parallel fiber synapses is observed with a loss of half of all these synapses. [16] Outside of the cerebellum the function of Cerebellin is still not clear.

LRRTMs

LRRTM is a postsynaptic protein that binds to neurexin at the same Ca2+ domain that neuroligin does despite having a distinct structure. [4] It has also been found that LRRTM binds AMPA receptors. [13] This is believed to be what causes the loss of excitatory signaling when LRRTM is not present. [17] Much is still not known about LRRTM even though it is the binding partner that binds to neurexin with the highest affinity. [18]

C1q1s

C1Q1's structure is similar to that of cerebellin as it is a small protein that is secreted that associates with multiple copies of itself. [13] C1q1 while in the synaptic cleft binds neurexin on the presynaptic side and BAI3 which is another adhesion G protein-coupled receptor. The deletion of c1q1 causes the loss of climbing fibers and excitatory signaling in general. [19] C1q1s are found broadly throughout the brain including the prefrontal cortex, amygdala, cerebellum, and potentially more. [20]

Species distribution

Members of the neurexin family are found across all animals, including basal metazoans such as porifera (sponges), cnidaria (jellyfish) and ctenophora (comb jellies). Porifera lack synapses so its role in these organisms is unclear.

Homologues of α-neurexin have also been found in several invertebrate species including Drosophila, Caenorhabditis elegans, honeybees and Aplysia. [12] In Drosophila melanogaster, NRXN genes (only one α-neurexin) are critical in the assembly of glutamatergic neuromuscular junctions but are much simpler. [6] Their functional roles in insects are likely similar to those in vertebrates. [21]

Role in synaptic maturation

Neurexin and neuroligin have been found to be active in synapse maturation and adaptation of synaptic strength. Studies in knockout mice show that the trans-synaptic binding team does not increase the number of synaptic sites, but rather increases the strength of the existing synapses. [12] Deletion of the neurexin genes in the mice significantly impaired synaptic function, but did not alter synaptic structure. This is attributed to the impairment of specific voltage gated ion channels. While neuroligin and neurexin are not required for synaptic formation, they are essential components for proper function. [12]

Clinical importance and applications

Recent studies link mutations in genes encoding neurexin and neuroligin to a spectrum of cognitive disorders, such as autism spectrum disorders (ASDs), schizophrenia, and mental retardation. [5] [22] Cognitive diseases remain difficult to understand, as they are characterized by subtle changes in a subgroup of synapses in a circuit rather than impairment of all systems in all circuits. Depending on the circuit, these subtle synapse changes may produce different neurological symptoms, leading to classification of different diseases. Counterarguments to the relationship between cognitive disorders and these mutations exist, prompting further investigation into the underlying mechanisms producing these cognitive disorders.

Autism

Autism is a neurodevelopmental disorder characterized by qualitative deficits in social behavior and communication, often including restricted, repetitive patterns of behavior. [23] It includes a subset of three disorders: childhood disintegrative disorder (CDD), Asperger syndrome (AS), and pervasive developmental disorder – not otherwise specified (PDD-NOS). A small percentage of ASD patients present with single mutations in genes encoding neuroligin-neurexin cell adhesion molecules. Neurexin is crucial to synaptic function and connectivity, as highlighted in wide spectrum of neurodevelopmental phenotypes in individuals with neurexin deletions. [22] This provides strong evidence that neurexin deletions result in increased risk of ASDs, and indicate synapse dysfunction as the possible site of autism origin. [24] Dr. Steven Clapcote et al.'s α-neurexin II (Nrxn2α) KO mice experiments demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice. [25]

Schizophrenia

Schizophrenia is a debilitating neuropsychiatric illness with multiple genes and environmental exposures involved in its genesis. [26] Further research indicates that deletion of the NRXN1 gene increases the risk of schizophrenia. [27] Genomic duplications and deletions on a micro-level – known as copy number variants (CNVs) – often underlie neurodevelopmental syndromes. Genomic-wide scans suggest that individuals with schizophrenia have rare structural variants that deleted or duplicated one or more genes. [26] As these studies only indicate an increased risk, further research is necessary to elucidate the underlying mechanisms of the genesis of cognitive diseases. [28]

Intellectual disability and Tourette syndrome

Similar to schizophrenia, studies have shown that intellectual disability and Tourette syndrome are also associated with NRXN1 deletions. [5] [26] A recent study shows that NRXN genes 1-3 are essential for survival and play a pivotal and overlapping role with each other in neurodevelopment. These genes have been directly disrupted in Tourette syndrome by independent genomic rearrangements. [29] Another study suggests that NLGN4 mutations can be associated with a wide spectrum of neuropsychiatric conditions and that carriers may be affected with milder symptoms. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. IPSPs were first investigated in motorneurons by David P. C. Lloyd, John Eccles and Rodolfo Llinás in the 1950s and 1960s. 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. Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a change in the permeability of the postsynaptic neuronal membrane to particular ions. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated, i.e. the postsynaptic membrane potential becomes more negative than the resting membrane potential, and this is called hyperpolarisation. To generate an action potential, the postsynaptic membrane must depolarize—the membrane potential must reach a voltage threshold more positive than the resting membrane potential. Therefore, hyperpolarisation of the postsynaptic membrane makes it less likely for depolarisation to sufficiently occur to generate an action potential in the postsynaptic neurone.

<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">Neuromuscular junction</span> Junction between the axon of a motor neuron and a muscle fiber

A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.

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.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

<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.

<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">LRRTM1</span> Protein-coding gene in the species Homo sapiens

LRRTM1 is a brain-expressed imprinted gene that encodes a leucine-rich repeat transmembrane protein that interacts with neurexins and neuroligins to modulate synaptic cell adhesion in neurons. As the name implies, its protein product is a transmembrane protein that contains many leucine rich repeats. It is expressed during the development of specific forebrain structures and shows a variable pattern of maternal downregulation.

<span class="mw-page-title-main">CASK</span> Protein-coding gene in humans

Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene. This gene is also known by several other names: CMG 2, calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.

<span class="mw-page-title-main">NRXN1</span> Protein-coding gene in the species Homo sapiens

Neurexin-1-alpha is a protein that in humans is encoded by the NRXN1 gene.

<span class="mw-page-title-main">SHANK1</span> Protein-coding gene in the species Homo sapiens

SH3 and multiple ankyrin repeat domains protein 1 is a protein that in humans is encoded by the SHANK1 gene.

<span class="mw-page-title-main">NLGN1</span> Protein-coding gene in the species Homo sapiens

Neuroligin-1 is a protein that in humans is encoded by the NLGN1 gene.

<span class="mw-page-title-main">DLGAP2</span> Protein-coding gene in the species Homo sapiens

Disks large-associated protein 2 is a protein that in humans is encoded by the DLGAP2 gene.

<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">Thomas C. Südhof</span> German-American biochemist

Thomas Christian Südhof, ForMemRS, is a German-American biochemist known for his study of synaptic transmission. Currently, he is a professor in the school of medicine in the department of molecular and cellular physiology, and by courtesy in neurology, and in psychiatry and behavioral sciences at Stanford University.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

Long-term potentiation (LTP), thought to be the cellular basis for learning and memory, involves a specific signal transmission process that underlies synaptic plasticity. Among the many mechanisms responsible for the maintenance of synaptic plasticity is the cadherin–catenin complex. By forming complexes with intracellular catenin proteins, neural cadherins (N-cadherins) serve as a link between synaptic activity and synaptic plasticity, and play important roles in the processes of learning and memory.

<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.

References

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