CHRNA2 Membrane Protein Introduction

Introduction of CHRNA2

CHRNA2, also known as neuronal acetylcholine receptor subunit alpha-2 (NACHRA2), is one of neuronal acetylcholine receptor (nAChR) subunits in humans and is encoded by the CHRNA2 gene. nAChRs are pentameric ligand-gated ion channels distributed widely throughout the nervous system. They modulate a wide range of activities in vertebrates and invertebrates. The activity and sensitivity of these receptors to particular pharmacological agents is determined by the subunit composition of the receptors. So far, 12 nAChR subunits have been identified (α2–α10 and β2–β4). Each subunit spans the plasma membrane with four transmembrane domains (M1–M4) and gives rise to several different nAChR subtypes in the brain, based on the subunit composition, all of which have their own unique biochemical, pharmacological, and biophysical characteristics.

Function of CHRNA2 Membrane Protein

The nAChRs modulate a wide range of physiological functions, such as sleep, arousal, anxiety, fatigue, and cognitive function. A heterozygous missense mutation, I279N, in the first transmembrane domain is crucial for receptor function. Electrophysiological research shows that CHRNA2 mutation alters the relative movements of the inner helices and outer shell during gating of the receptor and markedly increases the receptor sensitivity to acetylcholine (ACh). The ACh binding to α subunit triggers small concerted displacements in the extracellular domain, and these communicate to the membrane domain through the action of pushing against the β subunit, which tilts outwards in the membrane to open the pore. Furthermore, nAChR dysfunction is involved in a wide variety of diseases during development, adulthood, and aging. Finally, CHRNA2 is the third neuronal cholinergic receptor gene associated with familial sleep-related epilepsies. Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior.

Fig.1 Membrane topology of a neuronal nAChR subunit. (Hendrickson, 2013)

Application of CHRNA2 Membrane Protein Literature

1. Jun H., et al. An immune-beige adipocyte communication via nicotinic acetylcholine receptor signaling. Nature Medicine. 2018, 24(6):814-822. PubMed ID:29785025.
   
   

   This article reveals a beige-selective immune adipose interaction mediated through CHRNA2 and identifies a novel function of nicotinic acetylcholine receptors in energy metabolism.

2. Jin X., et al. Determination of the residues in the extracellular domain of the nicotinic α subunit required for the actions of physostigmine on neuronal nicotinic receptors. Molecular Pharmacology. 2017, 92(3):318-326. PubMed ID: 28630263.
   
   

   This article finds that receptors containing three copies of the α2 subunit are inhibited by low concentrations of physostigmine and point mutations could affect the extent of potentiation or inhibition.

3. Aridon P., et al. Increased sensitivity of the neuronal nicotinic receptor α2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. American Journal of Human Genetics. 2006, 79(2): 342–350. PubMed ID: 16826524.
   
   

   This article shows that the new CHRNA2 mutation markedly increases the receptor sensitivity to acetylcholine and CHRNA2 is the third neuronal cholinergic receptor gene associated with familial sleep-related epilepsies.

4. Wang H.Y., et al. Study of the interaction of chlorisondamine and chlorisondamine analogs with an epitope of the alpha-2 neuronal acetylcholine nicotinic receptor subunit. Journal of Proteome Research. 2005, 4(2):532-9. PubMed ID: 15822931.
   
   

   This article indicates three CHL analogs form noncovalent complexes with an epitope of the α2 nicotinic receptor subunit, GEREE(p)TEEEEEEEDEN, and all three analogs show better affinity than CHL for complex formation with both the nonphosphorylated and phosphorylated epitopes.

5. Bessis A., et al. Negative regulatory elements upstream of a novel exon of the neuronal nicotinic acetylcholine receptor α2 subunit gene. Nucleic Acids Research. 1993, 21(9):2185-92. PubMed ID: 8502560.
   
   

   This article indicates the expression of the CHRNA2 gene is highly restricted to the Spiriform lateral nucleus of the Chick diencephalon.

CHRNA2 Preparation Options

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Reference

1. Hendrickson L M, et al. (2013). Neuronal nicotinic acetylcholine receptors: common molecular substrates of nicotine and alcohol dependence. Frontiers in Psychiatry. 4, 29.

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