Alpha-4 beta-2 nicotinic receptor

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The alpha-4 beta-2 nicotinic receptor, also known as the α4β2 receptor, is a type of nicotinic acetylcholine receptor implicated in learning,[1] consisting of α4 and β2 subunits.[2] It is located in the brain, where activation yields post- and presynaptic excitation,[2] mainly by increased Na+ and K+ permeability.

Stimulation of this receptor subtype is also associated with growth hormone secretion. People with the inactive CHRNA4 mutation Ser248Phe are an average of 10 cm (4 inches) shorter than average and predisposed to obesity.[3] A 2015 review noted that stimulation of the α4β2 nicotinic receptor in the brain is responsible for certain improvements in attentional performance;[4] among the nicotinic receptor subtypes, nicotine has the highest binding affinity at the α4β2 receptor (ki=1 nM), which is also the primary biological target that mediates nicotine's addictive properties.[5]

The receptors exist in the two stoichiometries:

  • (α4)2(β2)3 receptors have high sensitivity to nicotine and low Ca2+ permeability (HS receptors)
  • (α4)3(β2)2 receptors have low sensitivity to nicotine and high Ca2+ permeability (LS receptors)

Structure[edit]

The x-ray structure of the (α4)2(β2)3 receptor is known since 2016[6] and reveals a circular α–β–β–α–β ordering of subunits.

Ligands[edit]

Agonists[edit]

PAMs[edit]

Antagonists[edit]

NAMs[edit]

See also[edit]

References[edit]

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  2. ^ a b Rang; Dale; Ritter; Moore (2003). Pharmacology (5th ed.). Churchill Livingstone. p. 138. ISBN 0-443-07145-4. 
  3. ^ Fedi, M; Bach, LA; Berkovic, SF; Willoughby, JO; Scheffer, IE; Reutens, DC (2008). "Association of a nicotinic receptor mutation with reduced height and blunted physostigmine-stimulated growth hormone release". The Journal of Clinical Endocrinology and Metabolism. 93 (2): 634–7. doi:10.1210/jc.2007-1611. PMID 18042647. 
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  5. ^ "Nicotine: Biological activity". IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 7 February 2016. Kis as follows; α2β4=9900nM [5], α3β2=14nM [1], α3β4=187nM [1], α4β2=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α4β2 is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction [2-3]. 
  6. ^ Morales-Perez CL, Noviello CM, Hibbs RE (2016). "X-ray structure of the human α4β2 nicotinic receptor". Nature. 538 (7625): 411–415. doi:10.1038/nature19785. PMID 27698419. 
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