Alpha5 Nicotinic Acetylcholine Receptor

The alpha-5 nicotinic acetylcholine receptor (α5 nAChR) also known as the α5 receptor is a type of ligand gated nicotinic acetylcholine receptor involved in pain regulation. One of the 5 transmembrane subunits of this receptor is the α5 subunit and is transcribed by the CHRNA5 gene. This receptor is commonly associated with nicotine addiction, immunotherapy, cancer, pain and attention.

Overview

There are two major classes of acetylcholine receptors: nicotinic (binds to exogenous nicotine) and muscarinic (binds exogenous muscarine). Nicotinic acetylcholine receptors (nAChRs) were initially discovered through the application and binding of nicotine, however, endogenous acetylcholine is the ligand that binds under normal physiological conditions. nAChRs are single channel ionotropic receptors found throughout the brain and body that allow for cations to flow in and out of cells. These receptors consist of five transmembrane subunits with the α5 nAChR defined by the presence of the α5 subunit. The α5 nAChR is located in various areas of the brain including the cortex, hippocampus, hypothalamus, inferior colliculus, medial habenula, olfactory bulb and striatum. The α5 nAChR is involved in modulating chronic inflammation and peripheral nerve injury.
Acetylcholine binds in the cortex, hippocampus, hypothalamus, inferior colliculus, striatum and olfactory bulb. CHRNA5 is located in a gene cluster on chromosome 15q24 along with CHRNA3 and CHRNB4. Homopentameric receptors with five acetylcholine binding sites contain two a-subunits (a2-a4 or a6) and two non-a-subunits (B2 or B4). Alpha5 subunits tend to be the fifth that does not directly bind to acetylcholine and act as auxiliary subunits. Rather, they may be important for receptor targeting and localization on the cell membrane. The alpha subunits normally assemble into both alpha3B4-containing and alpha4-beta2 containing nAChR assemblies. These receptors have been found on dopaminergic neurons in the rodent striatum and are involved in DA release upon nicotine stimulation. In addition to DA neurons, alpha5 subunits are also expressed on GABAergic neurons in the VTA and striatum.

Development

The alpha5 subunit is important during the development and maturation of prefrontal pyramidal IV neurons. Cholinergic dysfunction during development causes attentional deficits observed in diseases such as schizophrenia, neurodevelopmental disorders, autism and epilepsy. Most cholinergic neurons are developed by the perinatal period in humans. Maturational changes that occur in dendrites during development are absent in alpha5 -/- mice indicating that the alpha5 subunit is necessary for proper maturation of prefrontal pyramidal cells.

Nicotine Addiction and Withdrawal

Nicotine addiction is modulated by the mesocorticolimbic dopamine reward system that drives the rewarding nature of nicotine; the mesocorticolimbic system is involved in self-stimulation and processing an environmental reward. For example, this system is active while consuming highly caloric food or while gambling. Upon the administration of nicotine, there is increased firing rate mediated by midbrain dopamine neurons within this system. Through continuous exposure, dependence often occurs which is followed by withdrawal symptoms such as cravings, irritation, restlessness, sleep disturbances, weight gain, anxiety and difficulty concentrating. Subunits involved with withdrawal syndrome include α5, α2, and B4 within the epithalamic habenular complex and its projections. The medial habenula (MHb) and its projection to the interpeduncular nucleus (IPN) contain dense expression of α5 nAChR subunits.

''in vivo'' Studies

Studies have shown that removing the α5 nAChR subunits from mice (α5 nAChR null) will make them less sensitive to acute effects of nicotine. The mice showed decreased locomotion in an open field test and less nicotine-induced seizures. Other studies have shown that α5 nAChR null mice display fewer signs of dependency and reduced anxiety-like behaviors. Because the knockout mice show less aversion to increased nicotine intake, they tend to self-administer at much higher doses than wildtype mice. However, reintroduction of the alpha 5 subunit in the medial habenula in knockout mice restored normal levels of nicotine self-administration. This demonstrates that the expression of the alpha5 subunit in the medial habenula is sufficient to reinstate nicotine aversion. In contrast, the targeted knockdown of α5 subunits in the habenulo-interpeduncular pathway in wildtype mice did not change the stimulatory effects observed in knockout mice demonstrating that the subunit is not necessary for nicotine aversion, and that other areas of the brain can compensate for this behavior.

In a conditioned place preference study (CPP), researchers trained mice to associate nicotine administration with one chamber and saline administration in an adjacent chamber. At low doses of nicotine, alpha5 knockout mice and wildtype mice both showed preference for the nicotine chamber. However, at high doses of nicotine, only the α5 knockout mice preferred the nicotine chamber demonstrating that the alpha5 knockout mice still experienced the rewarding aspects of nicotine, but not the normal aversive behaviors with nicotine overdose.

Studies from Tuesta et al. 2011 have shown that the dose-response curve is similar when comparing knockout mice to wildtype mice however the knockout mice consumed greater amounts of nicotine which resulted in the descending portion of the dose-response curve to descend declined slower in the knockout mice. There has been shown an increased response to nicotine in the ascending portion of the curve demonstrating the greater rewarding properties.

Human Studies

Nicotine is commonly consumed by people for its rewarding properties resulting in dependence, addiction and withdrawal. Human studies have shown that people with a single nucleotide polymorphism (SNP) within the α5 nAChR encoding gene (CHRNA5, rs16969968) correlates with an increased risk of nicotine dependency and pleasure along with more heavy smoking. This particular SNP results in an aspartic acid to asparagine substitution at amino acid residue 398 (D398N). The rs16969968 within CHRNA5 causes a reduction in the receptor function that is involved in producing withdrawal symptoms. Individuals with this SNP are commonly found in those of European descent; there is about a 30% greater risk of nicotine dependence in individuals carry a single copy of the variant and about a 50% greater risk in individuals with two copies. Other studies have shown that people with this SNP develop nicotine dependence at a younger age. Researchers conclude that fewer aversive effects of nicotine would promote the rewarding effects or hedonic drive that would transition people from nicotine abuse to dependency. Additionally, SNP variants within rs16969968 in CHRNA5 have been associated with smoking related behaviors such has a higher prevalence of smokers vs nonsmokers.

Attention and cognition

Attention is an important aspect of memory that allows for information to be held in the mind and maintain focus in the presence of distractions in order to achieve a goal directed behavior. Working memory is a similar aspect of learning, however, the main difference between the two is that working memory requires the mental manipulation of information as well. The structure most commonly associated with attention is the prefrontal cortex that mediates top down control of complex cognitive processes. Acetylcholine is a neuromodulator that is closely studied for its role in learning and memory; it is involved in the acquisition, consolidation and recall.

''in vivo'' Studies

Researchers speculate that layer VI pyramidal neurons in the prefrontal cortex are important for holding attention in cognitively demanding tasks. These neurons send feedback projections to the thalamus and are highly responsive to acetylcholine.  In vivo studies have shown that the presence of alpha5 subunits of nAChRs on layer VI pyramidal neurons in the PFC are important for visual attention. In slice electrophysiology experiments, researchers have shown that alpha5 subunits enhance currents in the PFC of an adult mouse. In vivo, researchers use a five-choice serial reaction task. The animals are randomly given 1 of 5 light stimulus, and they need to encode and recall the location of the stimulus in order to receive a reward. Transgenic mice without the gene that encodes alpha5 subunits showed impaired performance on the five-choice serial reaction task. This indicates that the alpha5 null mice have attentional deficits. Interestingly, the deletion of alpha5 subunits in mice results in an upregulation of muscarinic acetylcholine receptors as an excitatory compensation response to circuitry dysfunction. Because of the cognitive enhancing effects of alpha5 nAChR agonists, it is a common target for neurodegenerative disorders with cognitive deficits along with ADHD.

Human Studies

Due to technical limitations of invasive procedures, there are far fewer studies in about the role of the alpha5 nAChR subunit and cognition. Studies have performed microdialysis in subjects as they formed attention tasks and found significantly increased acetylcholine efflux.

Clinical Application

The α5 nAChR mediates acute effects of alcohol; a deletion in this gene affects alcohol intake under stressful conditions. The α5 nAChR also mediates short term effects of nicotine. Studies have shown that removing the alpha5 subunit in mice (α5 nAChR knockdown) increases nicotine intake which is rescued by reintroducing the gene. Researchers have also shown that removing the α5 subunit only in the medial habenula increases nicotine self-administration, demonstrating that this subunit is necessary for normal nicotine intake and abnormalities within this subunit may contribute to the addictive properties of nicotine. Additionally, the alpha5 nAChR subunit is associated with other forms of addiction such as cocaine. Other studies have shown that α5 knockout mice shown impaired attentional performance. During high frequency vagal stimulation, α5 nAChR knockout mice experience impaired cardiac parasympathetic ganglionic transmission. ''in vivo'' studies have also identified the alpha5 nAChR as a possible treatment for chronic inflammation and neuropathic pain.

Ligands

References

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