CHRNA6

Cholinergic receptor, nicotinic, alpha 6, also known as nAChRα6, is a protein that in humans is encoded by the CHRNA6 gene.^[5] The CHRNA6 gene codes for the α6 nicotinic receptor subunit that is found in certain types of nicotinic acetylcholine receptors found primarily in the brain. α6 subunits cannot form homomeric receptors. Instead, they form heteromeric receptors along with other alpha or beta subunits. Different combinations of subunits create receptors with unique pharmacology.^[6]

CHRNA6
Identifiers
Aliases	CHRNA6, CHNRA6, cholinergic receptor nicotinic alpha 6 subunit
External IDs	OMIM: 606888; MGI: 106213; HomoloGene: 20888; GeneCards: CHRNA6; OMA:CHRNA6 - orthologs
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8p11.21 Start 42,752,620 bp[1] End 42,796,392 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8|8 A2 Start 27,893,240 bp[2] End 27,903,972 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle tibialis anterior muscle mucosa of ileum gonad cerebellar cortex deltoid muscle cerebellar hemisphere prefrontal cortex right hemisphere of cerebellum substantia nigra Top expressed in lumbar spinal ganglion neural layer of retina substantia nigra ventral tegmental area blastocyst central gray substance of midbrain Ileal epithelium superior colliculus pituitary gland embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function acetylcholine binding acetylcholine receptor activity ion channel activity extracellular ligand-gated ion channel activity ligand-gated ion channel activity protein binding acetylcholine-gated cation-selective channel activity transmembrane signaling receptor activity Cellular component integral component of membrane postsynaptic membrane membrane synapse cell junction plasma membrane acetylcholine-gated channel complex dopaminergic synapse integral component of postsynaptic membrane integral component of presynaptic membrane integral component of plasma membrane neuron projection Biological process regulation of dopamine secretion response to nicotine membrane depolarization synaptic transmission, cholinergic ion transport neuromuscular synaptic transmission signal transduction chemical synaptic transmission regulation of postsynaptic membrane potential excitatory postsynaptic potential cation transmembrane transport ion transmembrane transport regulation of synaptic vesicle exocytosis regulation of membrane potential nervous system process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8973 11440 Ensembl ENSG00000147434 ENSMUSG00000031491 UniProt Q15825 Q9R0W9 RefSeq (mRNA) NM_004198 NM_001199279 NM_021369 RefSeq (protein) NP_001186208 NP_004189 NP_067344 Location (UCSC) Chr 8: 42.75 – 42.8 Mb Chr 8: 27.89 – 27.9 Mb PubMed search [3] [4]
Wikidata
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Tissue distribution

α6-containing nicotinic acetylcholine receptors (nAChRs) show a restricted expression pattern in the brain. Neural nicotinic acetylcholine receptors containing α6 subunits are expressed on dopamine-releasing neurons in the midbrain.^[7][8] α6 nAChRs are primarily expressed in three regions: the Ventral Tegmental Area (VTA) and the Substantia Nigra (SN), which are both part of the midbrain dopaminergic system, and the Locus Coeruleus (LC), located in the brainstem.^[9]

Function

α6 nAChRs play a key role in regulating dopaminergic neurotransmission and respond to both nicotine and ethanol.

Nicotine

In the presence of nicotine, α6 nAChRs activate dopamine release in the VTA. This appears to take place through two mechanisms.

First, nicotine binds to α6 nAChRs on the axon terminals of presynaptic GABAergic neurons, which synapse onto postsynaptic dopaminergic neurons. Nicotine quickly desensitizes these receptors, preventing them from allowing Ca2+ to enter the axon terminal. Without Ca2+ to trigger neurotransmitter release, less GABA is released onto dopaminergic neurons. As a result, dopaminergic neurons are less inhibited, leading to more dopamine release.^[10][11]

Second, nicotine binds to and activates α6 nAChRs on dopaminergic neurons. In the dendrites, this causes excitatory depolarization, increasing the dopaminergic cells' firing rate. At the axon terminals, this allows Ca2+ to enter, facilitating neurotransmitter release. Together, these effects cause dopaminergic neurons to release more dopamine.^[9][12]

Dopamine release following activation of these neurons is thought to be involved in the addictive properties of nicotine.^[13][14][15] Studies in mice show that knocking out the α6 subunit causes mice to stop self-administering nicotine, while reintroducing the subunit reverses this result.^[16][17]

Ethanol

Ethanol modulates α6 nAChRs to cause dopamine release in the VTA.

In the VTA, low levels of ethanol increase dopamine release. Ethanol acts as a positive allosteric modulator by binding to α6 nAChRs on the axon terminals of GABAergic neurons outside the VTA, which connect to other GABAergic neurons within the VTA. ACh binding to these receptors causes Ca2+ influx into the upstream GABAergic neurons. Ethanol enhances this influx. This increases GABA release onto the VTA GABAergic neurons, inhibiting them and reducing their suppression of dopaminergic neurons. As a result, the dopaminergic neurons fire more rapidly, increasing dopamine release within the VTA^[9][18]

However, very high levels of ethanol actually reduce dopamine release. The exact mechanism for this is unknown.^[9][18]

In addition to nicotine, research in animals has implicated α6-containing nAChRs in the abusive and addictive properties of ethanol, with mecamylamine demonstrating a potent ability to block these properties.

Clinical significance

Because of their selective distribution and role in dopamine regulation in the Substantia Nigra, α6-containing receptors have been investigated as therapeutic targets. Due to their selective localisation on dopaminergic neurons, α6-containing nACh receptors have also been suggested as a possible therapeutic target for the treatment of Parkinson's disease.^[19][20]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

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Nicotine Activity on Dopaminergic Neurons edit

1. The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602".

See also

• Nicotinic acetylcholine receptor