Genomes and Genes
Gene Symbol: Chrna4
Description: cholinergic receptor nicotinic alpha 4 subunit
Alias: NARAC, neuronal acetylcholine receptor subunit alpha-4, Neuronal nicotinic acetylcholine receptor alpha 4 subunit, cholinergic receptor, nicotinic, alpha 4 (neuronal), cholinergic receptor, nicotinic, alpha polypeptide 4
- Quik M, Campos C, Bordia T, Strachan J, Zhang J, McIntosh J, et al. ?4?2 Nicotinic receptors play a role in the nAChR-mediated decline in L-dopa-induced dyskinesias in parkinsonian rats. Neuropharmacology. 2013;71:191-203 pubmed publisher..Since ?4?5?2 nAChRs are also predominantly on striatal dopamine terminals, these data suggest that drugs targeting ?4?2 nAChRs may reduce l-dopa-induced dyskinesias in late stage Parkinson's disease. ..
- Cesa L, Higgins C, Sando S, Kuo D, Levandoski M. Specificity determinants of allosteric modulation in the neuronal nicotinic acetylcholine receptor: a fine line between inhibition and potentiation. Mol Pharmacol. 2012;81:239-49 pubmed publisher..Our work has implications for rational drug design for nicotinic receptors and sheds light on mechanisms of allosteric modulation in nAChRs, especially the subtle differences between potentiation and inhibition. ..
- Jeanclos E, Lin L, Treuil M, Rao J, DeCoster M, Anand R. The chaperone protein 14-3-3eta interacts with the nicotinic acetylcholine receptor alpha 4 subunit. Evidence for a dynamic role in subunit stabilization. J Biol Chem. 2001;276:28281-90 pubmed..14-3-3 coimmunopurified with native alpha4 AChRs from brain. These results support a role for 14-3-3 in dynamically regulating the expression levels of alpha4beta2 AChRs through its interaction with the alpha4 subunit. ..
- Wu M, He Y, Guo F, Qi J. Alpha4beta2 nicotinic acetylcholine receptors are required for the amyloid beta protein-induced suppression of long-term potentiation in rat hippocampal CA1 region in vivo. Brain Res Bull. 2008;77:84-90 pubmed publisher..Thus, the present study provides further insight into the mechanisms by which Abeta impairs synaptic plasticity and cognitive function in the AD brain. ..
- Dobelis P, Marks M, Whiteaker P, Balogh S, Collins A, Stitzel J. A polymorphism in the mouse neuronal alpha4 nicotinic receptor subunit results in an alteration in receptor function. Mol Pharmacol. 2002;62:334-42 pubmed..The potential role of a single nucleotide polymorphism (SNP) in the nicotinic receptor alpha4 subunit gene (Chrna4) on nicotinic receptor binding and function in mice was also evaluated...
- Zhang H, Yu L, Eaton J, Whiteaker P, Onajole O, Hanania T, et al. Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective ?4?2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II. J Med Chem. 2013;56:5495-504 pubmed publisher..The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline. ..
- Schulz K, Andrud K, Burke M, Pearson J, Kreisler A, Stevens K, et al. The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring. Dev Neurobiol. 2013;73:806-14 pubmed publisher..Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness. ..
- Govind A, Walsh H, Green W. Nicotine-induced upregulation of native neuronal nicotinic receptors is caused by multiple mechanisms. J Neurosci. 2012;32:2227-38 pubmed publisher..We conclude that nicotine-induced upregulation is composed of multiple processes occurring at different rates with different underlying causes. ..
- Wang X. Nicotinic receptors partly mediate brainstem autonomic dysfunction evoked by the inhaled anesthetic isoflurane. Anesth Analg. 2009;108:134-41 pubmed publisher..The decrease of GABAergic IPSCs frequency is dependent upon inhibition of presynaptic alpha(4)beta(2) nicotinic receptors. ..
- Dehkordi O, Millis R, Dennis G, Jazini E, Williams C, Hussain D, et al. Expression of alpha-7 and alpha-4 nicotinic acetylcholine receptors by GABAergic neurons of rostral ventral medulla and caudal pons. Brain Res. 2007;1185:95-102 pubmed..The expression of alpha-4 and alpha-7 nAChRs by GAD67-ir cells suggests nicotinic cholinergic modulation of GABAergic signaling at these ventrolateral pontomedullary sites. ..
- Marritt A, Cox B, Yasuda R, McIntosh J, Xiao Y, Wolfe B, et al. Nicotinic cholinergic receptors in the rat retina: simple and mixed heteromeric subtypes. Mol Pharmacol. 2005;68:1656-68 pubmed
- Khakh B, Fisher J, Nashmi R, Bowser D, Lester H. An angstrom scale interaction between plasma membrane ATP-gated P2X2 and alpha4beta2 nicotinic channels measured with fluorescence resonance energy transfer and total internal reflection fluorescence microscopy. J Neurosci. 2005;25:6911-20 pubmed..The data provide direct evidence for the close spatial apposition of full-length P2X2 and alpha4beta2 channels within 100 nm of the plasma membrane of living cells. ..
- Xiao Y, Zhao L, Kuang S, Guan Z. Inhibited Expression of Î±4Î²2 Nicotinic Acetylcholine Receptor in Blood Leukocytes of Chinese Patients with Vascular Dementia and in Blood Leukocytes as Well as the Hippocampus of Brain from Ischemic Rats. Cell Mol Neurobiol. 2016;36:1377-1387 pubmed..These findings indicate that alterations in expression of the Î±4Î²2 subtype of nAChR may be involved in the molecular mechanism(s) underlying the cognitive deficit associated with VaD. ..
- Kim H, Flanagin B, Qin C, Macdonald R, Stitzel J. The mouse Chrna4 A529T polymorphism alters the ratio of high to low affinity alpha 4 beta 2 nAChRs. Neuropharmacology. 2003;45:345-54 pubmedPreviously, a missense polymorphism was identified in the mouse nicotinic receptor alpha4 subunit gene, Chrna4. This polymorphism leads to an Ala/Thr variation at amino acid position 529 of the alpha4 subunit...
- Steinlein O, Mulley J, Propping P, Wallace R, Phillips H, Sutherland G, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11:201-3 pubmed..2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref...
- Tsutsui Kimura I, Ohmura Y, Izumi T, Yamaguchi T, Yoshida T, Yoshioka M. Endogenous acetylcholine modulates impulsive action via alpha4beta2 nicotinic acetylcholine receptors in rats. Eur J Pharmacol. 2010;641:148-53 pubmed publisher..Substances that modulate nicotinic acetylcholine receptors, especially the alpha4beta2 subtype, may be beneficial for the treatment of psychiatric disorders characterized by lack of inhibitory control. ..
- Tsutsui Kimura I, Ohmura Y, Izumi T, Yamaguchi T, Yoshida T, Yoshioka M. Nicotine provokes impulsive-like action by stimulating alpha4beta2 nicotinic acetylcholine receptors in the infralimbic, but not in the prelimbic cortex. Psychopharmacology (Berl). 2010;209:351-9 pubmed publisher..The present results suggest a critical role for alpha4beta2 nAChRs in the IL in mediating the effects of nicotine on impulsive-like action in the 3-CSRTT. ..
- Tapper A, McKinney S, Nashmi R, Schwarz J, Deshpande P, Labarca C, et al. Nicotine activation of alpha4* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004;306:1029-32 pubmed..These data indicate that activation of a4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization. ..
- Elliott K, Ellis S, Berckhan K, Urrutia A, Chavez Noriega L, Johnson E, et al. Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits. J Mol Neurosci. 1996;7:217-28 pubmed
- Ren X, Cheng S, Treuil M, Mukherjee J, Rao J, Braunewell K, et al. Structural determinants of alpha4beta2 nicotinic acetylcholine receptor trafficking. J Neurosci. 2005;25:6676-86 pubmed..Collectively, our results identify, for the first time, residues within AChR subunits that are essential structural determinants of alpha4beta2 AChR ER export. ..
- Labarca C, Schwarz J, Deshpande P, Schwarz S, Nowak M, Fonck C, et al. Point mutant mice with hypersensitive alpha 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc Natl Acad Sci U S A. 2001;98:2786-91 pubmed..These knock-in mice provide useful insights into the pathophysiology of sustained nicotinic receptor activation and may provide a model for Parkinson's disease. ..
- Connolly J, Boulter J, Heinemann S. Alpha 4-2 beta 2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs. Br J Pharmacol. 1992;105:657-66 pubmed..Such an effect was not observed with promethazine, a related phenothiazine derivative which does not have antipsychotic actions. ..
- Quek G, Lin D, Halliday J, Absalom N, Ambrus J, Thompson A, et al. Identifying the binding site of novel methyllycaconitine (MLA) analogs at ?4?2 nicotinic acetylcholine receptors. ACS Chem Neurosci. 2010;1:796-809 pubmed publisher..Thus our data reveal distinct pharmacological differences between different nAChR subtypes and also identify a specific binding site for a noncompetitive channel blocker. ..
- Bordia T, Hrachova M, Chin M, McIntosh J, Quik M. Varenicline is a potent partial agonist at ?6?2* nicotinic acetylcholine receptors in rat and monkey striatum. J Pharmacol Exp Ther. 2012;342:327-34 pubmed publisher..These data suggest that the ability of varenicline to interact at ?6?2* nAChRs may contribute to its efficacy as a smoking cessation aid. ..
- Marubio L, Del Mar Arroyo Jimenez M, Cordero Erausquin M, Lena C, Le Novère N, de Kerchove d Exaerde A, et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature. 1999;398:805-10 pubmed..The alpha4 nAChR subunit, possibly associated with the beta2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception. ..
- Blum A, Lester H, Dougherty D. Nicotinic pharmacophore: the pyridine N of nicotine and carbonyl of acetylcholine hydrogen bond across a subunit interface to a backbone NH. Proc Natl Acad Sci U S A. 2010;107:13206-11 pubmed publisher..These data represent a completed nicotinic pharmacophore and offer insight into the design of new therapeutic agents that selectively target these receptors. ..
- Albuquerque E, Pereira E, Alkondon M, Rogers S. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev. 2009;89:73-120 pubmed publisher..Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy. ..
- Skok M, Grailhe R, Changeux J. Nicotinic receptors regulate B lymphocyte activation and immune response. Eur J Pharmacol. 2005;517:246-51 pubmed..This could contribute to immune depression found in tobacco smokers. ..
- Winterer G, Musso F, Konrad A, Vucurevic G, Stoeter P, Sander T, et al. Association of attentional network function with exon 5 variations of the CHRNA4 gene. Hum Mol Genet. 2007;16:2165-74 pubmed..by genetic variations within exon 5 of the alpha4 subunit of the nicotinergic acetylcholine receptor gene CHRNA4. The potential relevance of exon 5 is further emphasized by two recent family-based association studies of ..
- Forsayeth J, Kobrin E. Formation of oligomers containing the beta3 and beta4 subunits of the rat nicotinic receptor. J Neurosci. 1997;17:1531-8 pubmed..In this respect, nicotinic receptors that contain the beta3 subunit are structurally homologous to the muscle nicotinic receptor. ..
- Perez X, Bordia T, McIntosh J, Grady S, Quik M. Long-term nicotine treatment differentially regulates striatal alpha6alpha4beta2* and alpha6(nonalpha4)beta2* nAChR expression and function. Mol Pharmacol. 2008;74:844-53 pubmed publisher..Thus, alpha6beta2(*) nAChR subtypes may represent important targets for smoking cessation therapies and neurological disorders involving these receptors such as Parkinson's disease. ..
- Dourado M, Sargent P. Properties of nicotinic receptors underlying Renshaw cell excitation by alpha-motor neurons in neonatal rat spinal cord. J Neurophysiol. 2002;87:3117-25 pubmed..These findings support a role for alpha4beta2-like AChRs, but not alpha7 AChRs, in rapid excitatory transmission between alpha-motor neurons and Renshaw cells in rat spinal cord...
- Perry D, Xiao Y, Nguyen H, Musachio J, Dávila García M, Kellar K. Measuring nicotinic receptors with characteristics of alpha4beta2, alpha3beta2 and alpha3beta4 subtypes in rat tissues by autoradiography. J Neurochem. 2002;82:468-81 pubmed
- Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, et al. Nicotinic acetylcholine receptor immunohistochemistry in Alzheimer's disease and dementia with Lewy bodies: differential neuronal and astroglial pathology. J Neurol Sci. 2004;225:39-49 pubmed..Increased astrocyte alpha7 nAChRs in AD may be associated with inflammatory mechanisms related to degenerative processes specific to this disease. ..
- Cucchiaro G, Commons K. Alpha 4 nicotinic acetylcholine receptor subunit links cholinergic to brainstem monoaminergic neurotransmission. Synapse. 2003;49:195-205 pubmed
- Hales T, Dunlop J, Deeb T, Carland J, Kelley S, Lambert J, et al. Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and alpha4beta2 nicotinic acetylcholine receptors. J Biol Chem. 2006;281:8062-71 pubmed..This locus may be a common determinant of ion conduction throughout the Cys loop receptor family...
- Heeschen C, Weis M, Aicher A, Dimmeler S, Cooke J. A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J Clin Invest. 2002;110:527-36 pubmed..To our knowledge, this is the first description of a cholinergic angiogenic pathway, and it suggests a novel avenue for therapeutic modulation of angiogenesis. ..
- Mori T, Zhao X, Zuo Y, Aistrup G, Nishikawa K, Marszalec W, et al. Modulation of neuronal nicotinic acetylcholine receptors by halothane in rat cortical neurons. Mol Pharmacol. 2001;59:732-43 pubmed..Halothane block of nnAChRs is deemed to play an important role in anesthesia via a direct action on the receptor and an indirect action to suppress transmitter release. ..
- Wigestrand M, Mineur Y, Heath C, Fonnum F, Picciotto M, Walaas S. Decreased ?4?2 nicotinic receptor number in the absence of mRNA changes suggests post-transcriptional regulation in the spontaneously hypertensive rat model of ADHD. J Neurochem. 2011;119:240-50 pubmed publisher..Our results suggest that the lower ?4?2 nAChR number in SHR compared with WKY may be a consequence of dysfunctional post-transcriptional regulation of nAChRs. ..
- Xiu J, Nordberg A, Zhang J, Guan Z. Expression of nicotinic receptors on primary cultures of rat astrocytes and up-regulation of the alpha7, alpha4 and beta2 subunits in response to nanomolar concentrations of the beta-amyloid peptide(1-42). Neurochem Int. 2005;47:281-90 pubmed..We propose that the enhanced expression of alpha7, alpha4 and beta2 nAChRs by astrocytes stimulated directly by nanomolar concentrations of Abeta(1-42) might be related to ongoing defensive or compensative mechanisms. ..
- Lin L, Jeanclos E, Treuil M, Braunewell K, Gundelfinger E, Anand R. The calcium sensor protein visinin-like protein-1 modulates the surface expression and agonist sensitivity of the alpha 4beta 2 nicotinic acetylcholine receptor. J Biol Chem. 2002;277:41872-8 pubmed..Collectively, these results suggest that VILIP-1 represents a novel modulator of alpha4beta2 AChRs that increases their surface expression levels and agonist sensitivity in response to changes in the intracellular levels of calcium. ..
- Goldman D, Deneris E, Luyten W, Kochhar A, Patrick J, Heinemann S. Members of a nicotinic acetylcholine receptor gene family are expressed in different regions of the mammalian central nervous system. Cell. 1987;48:965-73 pubmed..Members of this gene family are expressed in different regions of the central nervous system and, presumably, code for subtypes of the nicotinic acetylcholine receptor. ..
- Lomazzo E, MacArthur L, Yasuda R, Wolfe B, Kellar K. Quantitative analysis of the heteromeric neuronal nicotinic receptors in the rat hippocampus. J Neurochem. 2010;115:625-34 pubmed publisher..Results suggested these subtypes have comparable binding affinities for the nicotinic ligands used here. ..
- Voitenko L, Voitenko S, Skok M, Purnyn H, Skok V. Nicotinic acetylcholine receptor subtypes in rat superior cervical ganglion neurons as studied by sequential application of two alpha-subunit-specific antibodies. Neurosci Lett. 2001;303:37-40 pubmed
- Klaassen A, Glykys J, Maguire J, Labarca C, Mody I, Boulter J. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc Natl Acad Sci U S A. 2006;103:19152-7 pubmed..To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4(S252F) and Chrna4(+L264)) in mice...
- Matsushima N, Hirose S, Iwata H, Fukuma G, Yonetani M, Nagayama C, et al. Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes. Epilepsy Res. 2002;48:181-6 pubmed
- Steensland P, Simms J, Holgate J, Richards J, Bartlett S. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A. 2007;104:12518-23 pubmed..The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence. ..
- Moore C, Wang Y, Ramage A. Cardiovascular effects of activation of central alpha7 and alpha4beta2 nAChRs: a role for vasopressin in anaesthetized rats. Br J Pharmacol. 2008;153:1728-38 pubmed publisher..These actions, although independent, are mediated by the central release of vasopressin. ..
- Todd R, Neuman R. Gene-environment interactions in the development of combined type ADHD: evidence for a synapse-based model. Am J Med Genet B Neuropsychiatr Genet. 2007;144B:971-5 pubmed..and child genotype in the development of attention deficit/hyperactivity disorder (ADHD), polymorphisms in the CHRNA4 gene were tested for interactions with prenatal smoking exposure on risk for ADHD subtypes using multiple logistic ..
- Xiao Y, Kellar K. The comparative pharmacology and up-regulation of rat neuronal nicotinic receptor subtype binding sites stably expressed in transfected mammalian cells. J Pharmacol Exp Ther. 2004;310:98-107 pubmed
- Krasteva G, Canning B, Hartmann P, Veres T, Papadakis T, Mühlfeld C, et al. Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci U S A. 2011;108:9478-83 pubmed publisher..This identifies brush cells as cholinergic sensors of the chemical composition of the lower airway luminal microenvironment that are directly linked to the regulation of respiration...
- Ibanez Tallon I, Miwa J, Wang H, Adams N, Crabtree G, Sine S, et al. Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron. 2002;33:893-903 pubmed