The neuronal acetylcholine receptor subunit alpha-5, or alpha-5 nicotinic acetylcholine receptor (α5 nAChR) also known as the α5 receptor is a type of ligand gated neuronal type subunit of the nicotinic acetylcholine receptor involved in pain regulation encoded in the human 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 receptors, which bind to exogenous nicotine, and muscarinic receptors, which bind 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. The 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 Addiction to nicotine 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 fewer 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.
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