Introduction of CHRNA4
CHRNA4, also known as the neuronal acetylcholine receptor subunit α-4 (NACRA4), is a transmembrane protein encoded by the CHRNA4 gene, which consists of six exons distributed over approximately 17 kb of genomic DNA. Neuronal acetylcholine receptors (nAChRs) are ligand-gated ion channels that, once activated, are permeable to sodium and calcium and cause cellular depolarization. They are pentamers variously composed of α subunits (α2–α10) and β subunits (β2–β4). The most common configuration contains α4 and β2 subunits. All nAChRs subunits have the same structural regions: a large N-terminal extracellular domain, the four transmembrane segments and connected by hydrophilic loops and a small C-terminal domain. The second transmembrane segment (M2) of each subunit is the main contributor to the formation of the ion channel. In mammals, α4β2 heteromeric receptors are highly expressed in most dopaminergic neurons of the midbrain dopamine pathways and their activation increases dopamine neuronal activity in the ventral tegmental area.
|Basic Information of CHRNA4|
|Protein Name||Neuronal acetylcholine receptor subunit alpha-4|
|Organism||Homo sapiens (Human)|
Function of CHRNA4 Membrane Protein
Activation of presynaptic nAChRs is known to facilitate the release of several neurotransmitters including γ-amino butyric acid (GABA), glutamate, dopamine and acetylcholine (ACh) itself. Heteromeric receptors α4β2-nAChRs are one of the predominant subtypes regulating dopamine neuronal firing and involved in dopaminergic mediated behaviors, such as drug reward and mood disorder. At the cellular level, the α4β2 nAChR has been shown to facilitate the release of a number of neurotransmitters including dopamine and γ-aminobutyric acid (GABA) and to excite cortical GABAergic interneurons. The intact α4 nAChR subunits provide partial protection against the proconvulsant effects of GABA antagonism in vivo. In addition, a defect in the α4/β2 mediated facilitation of GABA release would provide a plausible basis for epilepsy. The missense mutation in transmembrane domain 2 of CHRNA4 is associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in one extended pedigree. To date, five mutations have been identified in ADNFLE kindreds, and all mutations involve α4 or β2 subunit of the nAChRs.
Fig.1 The α4β2 nAChR contains two α4 subunits, two β2 subunits, and a fifth subunit that can be α4, β2, or another nAChR subunit. Two orthosteric (agonist-binding) sites are located in the extracellular domain of α4 and β2 subunit (represented by a docked ligand in red). (Mohamed, 2015)
Application of CHRNA4 Membrane Protein Literature
This article finds that receptors containing three copies of the α2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing three copies of the α4 subunit that are potentiated.
This article finds that the α5 subunit can occupy the position of a nonbinding subunit, or replace β2 subunit participating in a canonical binding site. The resulting receptors functionally resemble pentamers assembled with two copies of α5 and three copies of β2.
This article finds that hypersensitive α4 nicotinic receptors in mice mediate changes in the sleep-wake cycle and nicotine-induced seizures resembling ADNFLE.
This article indicates that a functional deletion of the α4 nAChR subunit in vivo is associated with a major increase in sensitivity to GABA receptor blockers.
This article shows that chrna4 RNA exhibits a widespread and robust expression pattern in the midbrain in 72 hpf and 96 hpf zebrafish.
CHRNA4 Preparation Options
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