CHRNA2

CHRNA2 gene encodes a protein used to make the so-called neuronal nicotinic acetylcholine receptor (nAChR). Neuronal nicotinic acetylcholine receptors (nAChRs) are homo- or hetero-pentamers. The heteropentamer channel is composed of α2-6 and β2-4 subunits, each nAChR protein consists of five subunits, usually two alpha (α) and three beta (β) subunits. The common subtype in the brain is α4β2, which is mainly expressed in the thalamus and cortex. These channels have a high affinity for acetylcholine and nicotine, and can penetrate Na + and (to a lesser extent) Ca²⁺ ions. Because of the channel predominantly express at presynaptic, it is believed that neuronal's nAChRs regulate the release of neurotransmitters, but how they affect neuronal networks is still poorly understood.

There may be many different combinations, and the characteristics of each nAChR protein depend on the type of subunits it contains. Among them, the CHRNA2 gene is responsible for the production of subunits called α2. Little is known about its specific function in nAChR protein.

In the brain, nAChR protein is widely distributed and plays an important role in the chemical signal conduction between nerve cells (neurons). These proteins act as ion channels on the plasma membrane, allowing charged atoms (ions) including calcium, sodium, and potassium to pass through the cell membrane. Studies have found that these channels are opened when they bind to a chemical substance called acetylcholine (neurotransmitter) released by the brain. In addition, studies have found that this channel also responds to the combination of nicotine (an addictive substance in tobacco), so it is considered to be related to tobacco addiction.

Communication between neurons depends on neurotransmitters, which are released from one type of neuron and absorbed by neighboring neurons. The release and absorption of these chemicals are strictly regulated to ensure the effective and accurate transmission of signals between neurons. Researchers believe that nAChR channels play an important role in controlling the normal release and uptake of neurotransmitters.

CHRNA2 and Disease

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Clinical studies have found that more functions of the brain depend on nAChR channels, including sleep and arousal, fatigue, anxiety, concentration, pain and memory. Studies have found that these channels are also active before the baby is born, indicating that they are involved in early brain development. So far, at least one drug targeting nAChR channels in the brain has been developed to help people quit smoking. Other drugs targeting these channels are under study, and they will be used to treat schizophrenia, Alzheimer's disease and pain.

Figure 1. Putative structure of the nAChR and position of the mutation I279N. (Hoda JC, et al.; 2009)

At least one mutation in the CHRNA2 gene has been found to cause autosomal dominant nocturnal frontal epilepsy (ADNFLE). The identified CHRNA2 mutation changes a single protein building block (amino acid) in the α2 subunit of the nAChR channel. Specifically, it replaced the amino acid isoleucine (Ile279Asn or I279N) with the amino acid asparagine at position 279 of the protein. This mutation makes the channels more sensitive to the neurotransmitter acetylcholine, making these ion channels easier to open than usual. The increase in ion current across the cell membrane will change the release of neurotransmitters, thereby changing the signal conduction between neurons. Researchers believe that the overexcitement of certain neurons in the brain triggers abnormal brain activity associated with seizures. It is not clear why seizures in ADNFLE start in the frontal lobe of the brain and occur most frequently during sleep.

References

1. Aridon P, et al.; Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet. 2006, 79(2):342-50.
2. Arneric SP, et al.; Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem Pharmacol. 2007, 74(8):1092-101.
3. Combi R, et al.; CHRNA2 mutations are rare in the NFLE population: evaluation of a large cohort of Italian patients. Sleep Med. 2009, 10(1):139-42.
4. Gu W, et al.; A major role of the nicotinic acetylcholine receptor gene CHRNA2 in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is unlikely. Neurosci Lett. 2007, 422(1):74-6.
5. Marini C, et al.; The role of the nicotinic acetylcholine receptors in sleep-related epilepsy. Biochem Pharmacol. 2007, 74(8):1308-14.
6. Hoda JC, et al.; Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene. FEBS Lett. 2009, 583(10):1599-604.