CHRNA6

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. 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.

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.

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.

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

Ethanol

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

However, very high levels of ethanol actually reduce dopamine release. The exact mechanism for this is unknown.

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.

Interactive pathway map

References

References

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