# CHRNA7

## Overview
The CHRNA7 gene encodes the cholinergic receptor nicotinic alpha 7 subunit (α7nAChR), a transmembrane protein that functions as a ligand-gated ion channel. This receptor is predominantly expressed in the central nervous system, where it plays a critical role in neurotransmission and cognitive processes such as learning and memory. The α7nAChR is characterized by its high permeability to calcium ions and rapid desensitization upon activation. It is involved in modulating synaptic plasticity and neurotransmitter release, influencing both presynaptic and postsynaptic neuronal activities. Beyond the central nervous system, α7nAChRs are also present in peripheral tissues, where they contribute to the regulation of inflammatory responses. The gene's location on chromosome 15q13.3 and its dosage sensitivity have been linked to various neuropsychiatric and neurological disorders, including schizophrenia, autism spectrum disorder, and epilepsy. The presence of a partial duplicate gene, CHRFAM7A, further complicates its genetic and functional landscape, impacting receptor function and associated clinical outcomes (Araud2011The; Sinkus2015The; Gillentine2015The).

## Structure
The CHRNA7 gene encodes the alpha 7 subunit of the nicotinic acetylcholine receptor, which is a ligand-gated ion channel. The primary structure of the CHRNA7 protein includes a sequence of amino acids that form various functional motifs and structural regions. Exon 1 encodes a signal peptide sequence, while exons 2, 4, and 5 contain putative glycosylation sites, which are common post-translational modifications that can affect protein folding and stability (Gault1998Genomic). The secondary structure likely includes alpha helices and beta sheets, typical of ion channel proteins, although specific details are not provided in the context.

The tertiary structure involves the 3D folding of the protein, which is crucial for its function as an ion channel. The CHRNA7 protein forms a homooligomeric channel with high calcium ion permeability, indicating a quaternary structure composed of multiple identical subunits (Yadav2017Homology). The protein features a ligand-binding domain, with potential competitive agonist binding sites located in exons 4, 6, and 7 (Gault1998Genomic). The transmembrane domains, responsible for forming the ion-conducting channel, are encoded by exons 7, 8, 9, and 10 (Gault1998Genomic). Splice variants of CHRNA7 may alter receptor function and expression, contributing to its role in neurological diseases (Araud2011The).

## Function
The CHRNA7 gene encodes the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel predominantly expressed in the brain. This receptor is involved in neurotransmission and plays a crucial role in modulating synaptic plasticity and cognitive functions, such as learning, memory, and attention (Sinkus2015The; Gillentine2017Functional). The α7nAChR is located on presynaptic terminals of GABAergic and glutamatergic neurons, where it facilitates the release of neurotransmitters like GABA, glutamate, acetylcholine, and dopamine through calcium influx (Sinkus2015The). Postsynaptically, it influences cognitive processes by affecting CREB phosphorylation and gene expression, enhancing cognitive circuits via an NR2B-NMDAR mechanism (Sinkus2015The).

In addition to its central nervous system functions, α7nAChRs are expressed in peripheral tissues, where they modulate inflammatory responses by preventing cytokine release (Sinkus2015The). The receptor's ion selectivity is regulated by glutamate residues in the intracellular face of the transmembrane region TM2, and it undergoes rapid desensitization following activation (Sinkus2015The). During development, α7nAChRs are expressed early in the hippocampus, influencing neuronal migration and dendritic formation (Sinkus2015The).

## Clinical Significance
The CHRNA7 gene, located on chromosome 15q13.3, is associated with several neuropsychiatric and neurological conditions due to its dosage sensitivity. Alterations in the copy number of CHRNA7, such as deletions or duplications, have been implicated in disorders including autism spectrum disorder (ASD), schizophrenia, intellectual disability, epilepsy, mood disorders, and attention deficit hyperactivity disorder (ADHD) (Gillentine2015The; Gillentine2017Functional). Deletions of CHRNA7 are generally associated with more severe phenotypes, such as cognitive deficits, seizures, and language impairments, while duplications are linked to conditions like ASD, ADHD, and schizophrenia (Gillentine2015The; Gillentine2016The).

The gene's involvement in these conditions is attributed to its role in neuronal signaling, particularly through the regulation of calcium flux, which is crucial for synaptic plasticity, learning, and memory (Gillentine2017Functional). The presence of the CHRFAM7A gene, a partial duplicate of CHRNA7, complicates the genetic landscape, as it can act as a dominant negative regulator of α7 nicotinic acetylcholine receptor function, further influencing the phenotypic outcomes (Araud2011The; Sinkus2015The). The variable expressivity and incomplete penetrance of these conditions suggest that additional genetic and environmental factors may modulate the clinical manifestations associated with CHRNA7 alterations (Gillentine2015The).

## Interactions
The CHRNA7 gene encodes the alpha-7 subunit of the nicotinic acetylcholine receptor, which is involved in various protein interactions that influence its function and role in neurological conditions. The CHRNA7 protein forms homooligomeric channels that are highly permeable to calcium ions and are sensitive to alpha-bungarotoxin, undergoing conformational changes upon binding acetylcholine (Yadav2017Homology). 

CHRNA7 interacts with several proteins, including JAK2, AKT1, and PICK1, which are associated with neurological diseases. The interaction with AKT1 is particularly significant as it regulates neuronal differentiation and development, highlighting CHRNA7's role in neurological conditions (Yadav2017Homology). 

The CHRNA7 gene can also undergo duplication and fusion with FAM7A, creating a hybrid gene CHRFAM7A, which produces a truncated subunit called Dupα7. This subunit negatively affects α7 receptor function and is linked to disorders like Alzheimer's and schizophrenia (Liu2021Structure). The presence of CHRFAM7A can lead to receptor sequestration in the endoplasmic reticulum and alter ligand binding sites, potentially resulting in receptors that cannot be activated by acetylcholine (Araud2011The). 

These interactions and modifications underscore the complex regulatory mechanisms governing CHRNA7 function and its implications in neuropsychiatric disorders.


## References


[1. (Gault1998Genomic) Judith Gault, Misi Robinson, Ralph Berger, Carla Drebing, Judith Logel, Jan Hopkins, Ted Moore, Suzette Jacobs, Jennifer Meriwether, Mun Jun Choi, Eun Jung Kim, Katy Walton, Karin Buiting, Ashley Davis, Charles Breese, Robert Freedman, and Sherry Leonard. Genomic organization and partial duplication of the human α7 neuronal nicotinic acetylcholine receptor gene (chrna7). Genomics, 52(2):173–185, September 1998. URL: http://dx.doi.org/10.1006/GENO.1998.5363, doi:10.1006/geno.1998.5363. This article has 314 citations and is from a peer-reviewed journal.](https://doi.org/10.1006/GENO.1998.5363)

[2. (Sinkus2015The) Melissa L. Sinkus, Sharon Graw, Robert Freedman, Randal G. Ross, Henry A. Lester, and Sherry Leonard. The human chrna7 and chrfam7a genes: a review of the genetics, regulation, and function. Neuropharmacology, 96:274–288, September 2015. URL: http://dx.doi.org/10.1016/j.neuropharm.2015.02.006, doi:10.1016/j.neuropharm.2015.02.006. This article has 142 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.neuropharm.2015.02.006)

[3. (Gillentine2015The) Madelyn A. Gillentine and Christian P. Schaaf. The human clinical phenotypes of altered chrna7 copy number. Biochemical Pharmacology, 97(4):352–362, October 2015. URL: http://dx.doi.org/10.1016/j.bcp.2015.06.012, doi:10.1016/j.bcp.2015.06.012. This article has 99 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.bcp.2015.06.012)

[4. (Yadav2017Homology) Ruchi Yadav, Deepshikha Deepshikha, and Prachi Srivastava. Homology modeling and protein interaction map of chrna7 neurogenesis protein. Annals of Neurosciences, 24(3):173–179, 2017. URL: http://dx.doi.org/10.1159/000477155, doi:10.1159/000477155. This article has 9 citations.](https://doi.org/10.1159/000477155)

[5. (Liu2021Structure) Danlin Liu, João V. de Souza, Ayaz Ahmad, and Agnieszka K. Bronowska. Structure, dynamics, and ligand recognition of human-specific chrfam7a (dupα7) nicotinic receptor linked to neuropsychiatric disorders. International Journal of Molecular Sciences, 22(11):5466, May 2021. URL: http://dx.doi.org/10.3390/ijms22115466, doi:10.3390/ijms22115466. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms22115466)

[6. (Araud2011The) Tanguy Araud, Sharon Graw, Ralph Berger, Michael Lee, Estele Neveu, Daniel Bertrand, and Sherry Leonard. The chimeric gene chrfam7a, a partial duplication of the chrna7 gene, is a dominant negative regulator of α7*nachr function. Biochemical Pharmacology, 82(8):904–914, October 2011. URL: http://dx.doi.org/10.1016/j.bcp.2011.06.018, doi:10.1016/j.bcp.2011.06.018. This article has 102 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.bcp.2011.06.018)

[7. (Gillentine2016The) M. A. Gillentine, L. N. Berry, R. P. Goin-Kochel, M. A. Ali, J. Ge, D. Guffey, J. A. Rosenfeld, V. Hannig, P. Bader, M. Proud, M. Shinawi, B. H. Graham, A. Lin, S. R. Lalani, J. Reynolds, M. Chen, T. Grebe, C. G. Minard, P. Stankiewicz, A. L. Beaudet, and C. P. Schaaf. The cognitive and behavioral phenotypes of individuals with chrna7 duplications. Journal of Autism and Developmental Disorders, 47(3):549–562, November 2016. URL: http://dx.doi.org/10.1007/s10803-016-2961-8, doi:10.1007/s10803-016-2961-8. This article has 62 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/s10803-016-2961-8)

[8. (Gillentine2017Functional) Madelyn A. Gillentine, Jiani Yin, Aleksandar Bajic, Ping Zhang, Steven Cummock, Jean J. Kim, and Christian P. Schaaf. Functional consequences of chrna7 copy-number alterations in induced pluripotent stem cells and neural progenitor cells. The American Journal of Human Genetics, 101(6):874–887, December 2017. URL: http://dx.doi.org/10.1016/j.ajhg.2017.09.024, doi:10.1016/j.ajhg.2017.09.024. This article has 51 citations.](https://doi.org/10.1016/j.ajhg.2017.09.024)