Biology:Neuroligin

From HandWiki
Short description: Protein
Neurolign and neurexin "handshake"
Neuroligin
Neuroligin4.png
Tertiary structure of Neuroligin 4.[1]
Identifiers
SymbolNeuroligin
InterProIPR000460
Membranome72
neuroligin 1
Identifiers
SymbolNLGN1
NCBI gene22871
HGNC14291
OMIM600568
RefSeqNP_055747
UniProtQ8N2Q7
Other data
LocusChr. 3 q26.31
neuroligin 2
Identifiers
SymbolNLGN2
NCBI gene57555
HGNC14290
OMIM606479
RefSeqNP_065846
UniProtQ8NFZ4
Other data
LocusChr. 17 p13.1
neuroligin 3
Identifiers
SymbolNLGN3
NCBI gene54413
HGNC14289
OMIM300336
RefSeqNP_001160132
UniProtQ9NZ94
Other data
LocusChr. X q13.1
neuroligin 4X
Identifiers
SymbolNLGN4X
NCBI gene57502
HGNC14287
OMIM300427
RefSeqNP_065793
UniProtQ8N0W4
Other data
LocusChr. X p22.32-22.31

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.[2] 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.[3] Additionally, neuroligins are expressed in human peripheral tissues and have been found to play a role in angiogenesis.[4] In humans, alterations in genes encoding neuroligins are implicated in autism and other cognitive disorders.[5] Antibodies in a mother from previous male pregnancies against neuroligin 4 from the Y chromosome increase the probability of homosexuality in male offspring.

Structure

Neuroligins bind with the aid of Ca2+ to the α-neurexin LNS (laminin, neurexin and sex hormone-binding globulin-like folding units) domains and to the β-neurexin LNS domain which then establishes a heterophilic trans-synaptic recognition code.[6] Through the observation of the crystal structure of neuroligin-1, it was determined that neuroligin-1 forms a protein dimer when two neurexin-1 beta monomers bind to the neuroligin-1's two opposite surfaces. This forms a heterotetramer, which contains an interface for binding Ca2+. The interaction of neuroligin and neurexin to form a heterotetramer is monitored by alternatively spliced sites located near the binding interface for Ca2+ in both the neuroligin-1 and the neurexin-1 beta.[7] Subsequently, the presence of native neuroligin dimers was confirmed in neurons through biochemical detection, which included heterodimers composed of different neuroligin species,[8] increasing the potential heterogeneity of endogenous neuroligin core dimer complexes.

The extracellular domain of NLGN consists mostly of a region that is homologous to acetylcholinesterases, but the amino acids important for catalysis in AChE are not conserved in NLGN, which lack esterase activity. Furthermore, this AChE homologous region is crucial for the proper function of NLGN.[2]

Genetics

Neuroligins have been identified in both vertebrates and invertebrates, including humans, rodents, chickens, Drosophila melanogaster, Caenorhabditis elegans, honeybees and Aplysia. Three genes for neuroligin expression have been found in mice and rats, while humans express five genes.[9] Drosophila express four genes, honeybees express five genes, and both C. elegans and Aplysia express a single gene for neuroligin.[10]

The known neuroligin genes in Homo sapiens include NLGN1, NLGN2, NLGN3, NLGN4X and NLGN5 (also known as NLGN4Y). Each gene has been found to have unique influences on synaptic transmission.

Expression

Expression of neuroligins may differ between species. Neuroligin 1 is expressed specifically in the CNS at excitatory synapses. In humans, expression of neuroligin 1 is low before birth and increases between postnatal days 1-8 and remains high through adulthood. This postnatal increase during active synaptogenesis corresponds to increased expression of postsynaptic density protein-95 (PSD-95). Neuroligin 2 is mainly concentrated at inhibitory synapses in the CNS, but in mice and humans it may also be expressed in tissues such as the pancreas, lung, endothelia, uterus and colon. Neuroligin 3 is expressed in CNS neurons, as well as a variety of glial cells in mice and rats and the brain, heart, skeletal muscle, placenta and pancreas in humans. Neuroligin 4X is expressed in the heart, liver, skeletal muscle, pancreas and low levels in the brain. Neuroligin 5 (or 4Y), located on the Y chromosome, is only 19 amino acids different from neuroligin 4X.[9] Neuroligin mRNA are present in human endothelial cells from large blood vessels [11] and in Dorsal Root Ganglions.[12]

Alternative splicing

Alternative splicing, a modification that occurs after transcription of mRNA, regulates neuroligins’ binding selectivity for α- or β-neurexins as well as the function of synapses. Alternative splicing in neuroligins occurs in the main functional domain, the acetylcholinesterase-homologous region.[13] Because neuroligin has two conserved splice sites in this region, sites A and B, up to four different isoforms are possible for each neuroligin gene.[9] Neurexins also undergo alternative splicing, and certain splice variants of neuroligins and neurexins are more selective for one another. Specific pairing of splice variants also affects synaptic function. For example, neuroligins lacking the B splice insert and β-neurexins with the S4 insert promote differentiation of inhibitory, GABAergic synapses. On the other hand, neuroligins with the B insert and β-neurexins lacking the S4 insert promote differentiation of excitatory, glutamatergic synapses. The A insert may promote neuroligin localization and function at inhibitory synapses, but the mechanisms are unknown.[13]

Activity with neurexin

Neurexin and neuroligin work together to gather and maintain the cytoskeleton components needed to localize synaptic vesicles. Neurexin is necessary for containing the voltage-gated Ca2+ channels that are required for the release of vesicles, while neuroligin binds neurexin in order to localize the necessary neurotransmitter receptors and proteins for postsynaptic specialization. At the postsynaptic site, neuroligins are networked to specialized proteins that stimulate specific neurotransmitter receptors and channels to densely occupy specialized regions of the postsynaptic terminal during the maturation of the synapse. Because all developing synapses contain neurexins and neuroligins, developing cells can make many different connections to other cells.[3]

Synapse formation

Neuroligin is sufficient to form new functional presynaptic terminals in vitro.[9] However, evidence suggests that additional adhesion molecules, such as immunoglobulin-domain and cadherin family proteins, mediate the initial contact between the axons and dendrites for a synapse. Neurexins and neuroligins then reinforce the contact.[13]

In addition to the selectivity of splice variants, the levels of neuroligins, neurexins, and other interacting proteins present on the pre- and postsynaptic membranes influence the differentiation and balance of synapses. As synapses form during synaptogenesis, they differentiate into one of two categories: excitatory or inhibitory. Excitatory synapses increase probability of firing an action potential in the postsynaptic neuron and are often glutamatergic, or synapses in which the neurotransmitter glutamate is released. Inhibitory synapses decrease probability of firing an action potential in the postsynaptic neuron and are often GABAergic, in which the neurotransmitter GABA is released. Especially during early development, neurons must receive an appropriate balance of excitatory vs. inhibitory synaptic input, referred to as the E/I ratio. In fact, an imbalance in the E/I ratio is thought to be involved in autistic spectrum disorders.[14]

Neuroligin 1 localizes at excitatory synapses, neuroligin 2 at inhibitory synapses and neuroligin 3 at both. Reduction in the levels of neuroligins 1, 2 and 3 results in a strong reduction of inhibitory input but little reduction in excitatory input.[13] In addition, Neuroligins interacts with PSD-95, an intracellular protein that anchors synaptic proteins in the post-synaptic density of excitatory synapses, and gephyrin, the respective scaffolding protein of inhibitory post-synapses.[15] In addition, neuroligin 2 and 4 specifically interact with collybistin a protein that regulates the localization of gephyrin. The level of PSD-95 appears to influence the balance of excitatory and inhibitory inputs. An increase in the ratio of PSD-95 to neuroligin resulted in an increase in the E/I ratio, and a decrease in the PSD-95/neuroligin ratio had the opposite effect.[14] Also, overexpression of PSD-95 redirects neuroligin-2 from excitatory to inhibitory synapses, strengthening excitatory input and reducing inhibitory input.[13] These interactions of neuroligin, neurexin and interacting proteins such as PSD-95 point to a potential regulatory mechanism that controls development and balance of excitatory and inhibitory synapses, governed by homeostatic feedback mechanisms.[14]

Clinical significance

Neuroligin dysfunction has been implicated in autism spectrum disorders. Different genetic alterations have been detected in neuroligin genes in patients with ASD, including point mutations, missense mutations and internal deletions.[11] In studies done on family members with X-linked autism, specific mutations of NLGN3 and NLGN4 have been identified. These mutations have been shown to affect how neuroligins function and have been shown to interfere with synaptic transmission. 19 of the 69 known proteins mutated in X-linked autism encode postsynaptic proteins, Neuroligins included.

Additionally, maternal antibodies against Y-chromosome neuroligin NLGN4Y have been implicated in the fetal development of male homosexuality.[16]

NLGN3 mutations

A mutated NLGN3 gene, R451C, has been cloned. The mutant has been shown to cause defective neuroligin trafficking and retention of the mutant protein in the endoplasmic reticulum.[17] The small amount of mutant protein that reached the cell membrane demonstrated diminished binding activity for neurexin-1, consistent with a loss of function.[18] The mutant gene has been cloned and was introduced into mice, resulting in impaired social interactions, enhanced spatial learning abilities and increased inhibitory synaptic transmission. Deleting NLGN3 did not produce these effects, thus indicating R451C to be a gain-of-function mutation. This supports the claim that increased inhibitory synaptic transmission may contribute to human autism spectrum disorders.[19]

NLGN4 mutations

Mutations in NLGN4 have also been found in persons with X-linked autism. A frame shift mutation 1186T has been found to cause an early stop codon and premature protein truncation. This mutation results in intracellular retention of mutant proteins, possibly causing impaired function of a synaptic cell adhesion molecule,[17] and modifying the binding of the neuroligin protein to its presynaptic partners, neurexins, thus interrupting essential synaptic function.[20] Other mutations of NLGN4 found in relation to autism spectrum disorders include a 2-bp deletion, 1253delAG, in the NLGN4 gene, which causes a frameshift and a premature stop codon.[21] Another mutation is a hemizygous deletion in the NLGN4 gene encompassing exons 4, 5 and 6. The 757-kb deletion was predicted to result in a significantly truncated protein.[22]

See also

References

  1. ↑ "Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion". Neuron 56 (6): 979–91. December 2007. doi:10.1016/j.neuron.2007.11.013. PMID 18093521. 
  2. ↑ 2.0 2.1 "Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons". Cell 101 (6): 657–69. June 2000. doi:10.1016/S0092-8674(00)80877-6. PMID 10892652. 
  3. ↑ 3.0 3.1 Purves, Dale; Augustine, George; Fitzpatrick, David; Hall, William C.; LaMantia, Anthony-Samual; White, Leonard E. (2012). Neuroscience Fifth Edition. Sunderland, MA: Sinauer Associates. pp. 521–522. ISBN 978-0-87893-695-3. 
  4. ↑ "The synaptic proteins neurexins and neuroligins are widely expressed in the vascular system and contribute to its functions". Proceedings of the National Academy of Sciences of the United States of America 106 (49): 20782–7. December 2009. doi:10.1073/pnas.0809510106. PMID 19926856. Bibcode: 2009PNAS..10620782B. 
  5. ↑ "Neuroligins and neurexins link synaptic function to cognitive disease". Nature 455 (7215): 903–11. October 2008. doi:10.1038/nature07456. PMID 18923512. Bibcode: 2008Natur.455..903S. 
  6. ↑ "Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion". Neuron 56 (6): 979–91. December 2007. doi:10.1016/j.neuron.2007.11.013. PMID 18093521. 
  7. ↑ "Structures of neuroligin-1 and the neuroligin-1/neurexin-1 beta complex reveal specific protein-protein and protein-Ca2+ interactions". Neuron 56 (6): 992–1003. December 2007. doi:10.1016/j.neuron.2007.12.002. PMID 18093522. 
  8. ↑ "Homodimerization and isoform-specific heterodimerization of neuroligins". The Biochemical Journal 446 (2): 321–30. September 2012. doi:10.1042/BJ20120808. PMID 22671294. https://zenodo.org/record/3427087. 
  9. ↑ 9.0 9.1 9.2 9.3 "The neuroligin and neurexin families: from structure to function at the synapse". Cellular and Molecular Life Sciences 63 (16): 1833–49. August 2006. doi:10.1007/s00018-006-6061-3. PMID 16794786. 
  10. ↑ "Neurexins and neuroligins: recent insights from invertebrates". Molecular Neurobiology 44 (3): 426–40. December 2011. doi:10.1007/s12035-011-8213-1. PMID 22037798. 
  11. ↑ 11.0 11.1 "Neurexins and neuroligins: synapses look out of the nervous system". Cellular and Molecular Life Sciences 68 (16): 2655–66. August 2011. doi:10.1007/s00018-011-0664-z. PMID 21394644. 
  12. ↑ "Gephyrin clusters are absent from small diameter primary afferent terminals despite the presence of GABA(A) receptors". The Journal of Neuroscience 34 (24): 8300–17. June 2014. doi:10.1523/JNEUROSCI.0159-14.2014. PMID 24920633. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 "Neurexin-neuroligin signaling in synapse development". Current Opinion in Neurobiology 17 (1): 43–52. February 2007. doi:10.1016/j.conb.2007.01.011. PMID 17275284. 
  14. ↑ 14.0 14.1 14.2 "Building excitatory and inhibitory synapses: balancing neuroligin partnerships". Neuron 48 (2): 171–4. October 2005. doi:10.1016/j.neuron.2005.09.017. PMID 16242398. 
  15. ↑ "Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin". Neuron 63 (5): 628–42. September 2009. doi:10.1016/j.neuron.2009.08.023. PMID 19755106. 
  16. ↑ "Male homosexuality and maternal immune responsivity to the Y-linked protein NLGN4Y". Proceedings of the National Academy of Sciences of the United States of America 115 (2): 302–306. January 2018. doi:10.1073/pnas.1705895114. PMID 29229842. Bibcode: 2018PNAS..115..302B. 
  17. ↑ 17.0 17.1 "Disorder-associated mutations lead to functional inactivation of neuroligins". Human Molecular Genetics 13 (14): 1471–7. July 2004. doi:10.1093/hmg/ddh158. PMID 15150161. 
  18. ↑ "The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing". The Journal of Neuroscience 24 (20): 4889–93. May 2004. doi:10.1523/JNEUROSCI.0468-04.2004. PMID 15152050. 
  19. ↑ "A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice". Science 318 (5847): 71–6. October 2007. doi:10.1126/science.1146221. PMID 17823315. Bibcode: 2007Sci...318...71T. 
  20. ↑ "Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism". Nature Genetics 34 (1): 27–9. May 2003. doi:10.1038/ng1136. PMID 12669065. 
  21. ↑ "The role of neuronal complexes in human X-linked brain diseases". American Journal of Human Genetics 80 (2): 205–20. February 2007. doi:10.1086/511441. PMID 17236127. 
  22. ↑ "Familial deletion within NLGN4 associated with autism and Tourette syndrome". European Journal of Human Genetics 16 (5): 614–8. May 2008. doi:10.1038/sj.ejhg.5202006. PMID 18231125. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Neuroligin&oldid=3553123"