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Date
10/11/2011 15:29:40
Group number
PI name
Criado, M.
Channel family
Nicotinic Acetylcholine Receptor
Channel name
Alpha7 nAChR
Channel subunit
Alpha7
UNIPROT
Relevant publication (1)
García-Guzmán et al.(1995) Alpha-Bungarotoxin-sensitive nicotinic receptors on bovine chromaffin cells: molecular cloning, functional expression and alternative splicing of the alpha7 subunit. Eur. J. Neurosci. 7, 647-655
Relevant publication (2)
Domínguez del Toro, E., et al.(1994) Immunocytochemical localization of the alpha7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system. J. Comp. Neurol. 347, 325-342.
Relevant publication (3)
Criado, M. et al. (1997) Differential expression of alpha-bungarotoxin-sensitive neuronal nicotinic receptors in adrenergic chromaffin cells: a role for transcription factor Egr-1. J. Neurosci. 17, 6554-6564.
CD
FTIR
NMR
Absorbance /
Fluorescence
Interaction protein (1)
RIC-3 (Castillo, M. et al. (2005) A dual role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors. J. Biol. Chem. 280, 27062-27068)
Interaction protein (2)
Interaction protein (3)
Interaction protein (4)
PDB (1)
PDB (2)
PDB (3)
Expression tissues
Broadly expressed at the CNS (Dominguez del Toro, E. et al. (1994) Immunocytochemical localization of the alpha7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system. J. Comp. Neurol. 347, 325-342.);PNS (Criado, M., et al. (1997) Differential expression of alpha-bungarotoxin-sensitive neuronal nicotinic receptors in adrenergic chromaffin cells: a role for transcription factor Egr-1. J. Neurosci. 17, 6554-6564) and non-neuronal tissues (Bencherif, M. et al. (2011) Alpha7 nicotinic receptors as novel therapeutic targets for inflammation- based diseases.Cell Mol Life Sci. 68, 931-949.)
Expression cell lines
SH-SY5Y e IMR-32 (Groot Kormelink P.J., Luyten W.H.M.L. (1997)Cloning and sequence of full-length cDNAs encoding the human neuronal nicotinic acetylcholine receptor (nAChR) subunits beta3 and beta4 and expression of seven nAChR subunits in the human neuroblastoma cell line SH-SY5Y and/or IMR-32. FEBS Lett.400, 309-314.

PC-12 (Nery A.A., et al (2010) Alpha 7 nicotinic acetylcholine receptor expression and activity during neuronal differentiation of PC12 pheochromocytoma cells. J Mol Neurosci. 41, 329-339
Expression plasmids
pSP64T (oocyte expression García-Guzmán, M., et al.. (1995) alpha-Bungarotoxin-sensitive nicotinic receptors on bovine chromaffin cells: molecular cloning, functional expression and alternative splicing of the alpha7 subunit. Eur. J. Neurosci. 7, 647-655.)
Level of expression
Variable, depending of each mutant. Too many mutants to be described here (see references in 9.4.)
Channel quaternary
Pentamer
Agonists
Acetylcholine, Nicotine, Epibatidine, Cytisine (General agonists)
A-833834 (specific alpha7 agonist) (Li J. et al. (2010) Role of a7 nicotinic acetylcholine receptors in regulating tumor necrosis factor-a (TNF-a) as revealed by subtype selective agonists. J Neuroimmunol. 2011 Sep 10. [Epub ahead of print]).
Review: Toyohara J, Hashimoto K. (2010) a7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer's Disease. Open Med Chem J. 27;4:37-56.
Smile agonist
Antagonists and blockers
alpha-bungarotoxin
methyllycaconitine (MLA) (Hahn B, et al. (2011) Selective nicotinic receptor antagonists: effects on attention and nicotine-induced attentional enhancement. Psychopharmacology 217, 75-82.
Smile antagonist
Structure-function
relationship
Amino acids located in different loops and beta-strands affect coupling between binding and gating of receptors as follows:

1. Loops 2, 7 and M2-M3 linker (Campos-Caro, A., et al. (1996) A single residue in the M2-M3 loop is a major determinant of coupling between binding and gating in neuronal nicotinic receptors. Proc. Natl. Acad. Sci. USA 93, 6118-6123. Sala, F., et al. (2005) Charged amino acids of the N-terminal domain are involved in coupling binding and gating in alpha7 nicotinic receptors. J. Biol. Chem. 280, 6642-6647. Aldea, M., et al. (2007) Non-charged amino acids from three different domains contribute to link agonist binding to channel gating in alpha7 nicotinic acetylcholine receptors. J. Neurochem. 103, 725-735.

2. Loop 5 and beta-strand beta6' (Criado, M., Mulet, J., Castillo, M., Aldea, M., Sala, S., Sala, F. (2008) Interactions between loop 5 and beta-strand beta6’ are involved in alpha7 nicotinic acetylcholine receptors channel gating. J. Neurochem. 104, 719-730)

3. Loop 9 (Criado, M., et al. (2010) Role of loop 9 on the function of neuronal nicotinic receptors. Biochim. Biophys. Acta Biomembranes 1798, 654-659).

4. Pore domain (Criado, M., et al. (2011) Substitutions of amino acids in the pore domain of homomeric alpha7 nicotinic receptors for analogous residues present in heteromeric receptors modify gating, rectification and binding properties. J. Neurochem. 119, 40-49).

5. Regions close to the binding site (Criado, M., et al. (2005) Mutations of a conserved lysine residue in the N-terminal domain of alpha7 nicotinic receptors affect binding and gating of nicotinic agonists. Mol. Pharmacol. 68, 1669-1677. Criado, M., et al. (2011) Mutants of beta-strand beta3 and the loop B in the interface between alpha7 subunits of a homomeric acetylcholine receptor show functional and pharmacological alterations. J. Neurochem. 118, 968-978).

See General Reviews:
Miller, P.S. and Smart, T.G. (2010) Binding, activation and modulation of Cysloop
receptors. Trends Pharmacol. Sci. 31, 161–174.
Albuquerque, E.X., et al. (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol. Rev. 89, 73–109.
Molecular determinant assembly
Amino acids at the N-terminal region influence pentameric assembly (Castillo, M., et al.(2009) Role of the N-terminal alpha-helix in biogenesis of alpha7 nicotinic receptors. J. Neurochem. 108, 1399-1409. 92. Criado, M., et al.(2010) The loop between beta-strands beta2 and beta3 and its interaction with the N-terminal alpha-helix is essential for biogenesis of alpha7 nicotinic receptors. J. Neurochem. 112, 103-111).

See General Review: Tsetlin, V., et al. (2011) Assembly of nicotinic and other Cys-loop receptors. J. Neurochem. 116, 734–741.
Molecular determinant clustering
Sequences that target alpha7 and other nicotinic receptors to dendrites and axons (Xu, J., et al. (2006) Identification of Sequence Motifs That Target Neuronal Nicotinic Receptors to Dendrites and Axons. J. Neurosci. 26, 9780 –9793.).
Molecular determinant trafficking
Amino acids of the large cytoplasmic loop affect receptor biogenesis in different ways during assembly mainly trafficking ( Castelán, F., et al. (2007) Cytoplasmic regions adjacent to the M3 and M4 transmembrane segments influence expression and function of alpha7 nicotinic acetylcholine receptors. A study with single amino acid mutants. J. Neurochem. 100, 406-415. 96. Criado, M.,et al. (2011) A small cytoplasmic region adjacent to the fourth transmembrane segment of the alpha7 nicotinic receptor is essential for its biogenesis. FEBS Lett. 585, 2477-2480.)
See General Review: Millar, N.S. and Harkness, P.C. (2008) Assembly and trafficking of nicotinic acetylcholine receptors. Mol. Membr. Biol. 25, 279–292.
Molecular determinant binding
The use of crystallized acetylcholine binding proteins as models for other nicotinic receptors (Rucktooa, P. et al. (2009) Insight in nAChR subtype selectivity from AChBP crystal structures. Biochem. Pharmacol. 78, 777-787.)
Structural basis of alpha7 receptor potentiation (Dacosta C.J. at al. (2011) Single-Channel and Structural Foundations of Neuronal {alpha}7 Acetylcholine Receptor Potentiation. J. Neurosci. 31,13870-13879
A crystalline structure of a chimeric receptor made of the acetylcholine binding protein and the alpha 7 receptor (extracellular region). (Li, S.-X. et al. (2011) Ligand-binding domain of an a7-nicotinic receptor chimera and its complex with agonist. Nature Neurosci. 14,1253–1259)
Mutants constructs
1. Green fluorescent protein attached to C-terminus (Castillo, M., et al.(2005) A dual role of the RIC-3 protein in trafficking of serotonin and nicotinic acetylcholine receptors. J. Biol. Chem. 280, 27062-27068).

2. Mutants of loops 2, 7 and M2-M3 linker (Sala, F., et al. (2005) Charged amino acids of the N-terminal domain are involved in coupling binding and gating in alpha7 nicotinic receptors. J. Biol. Chem. 280, 6642-6647. Aldea, M., et al. (2007) Non-charged amino acids from three different domains contribute to link agonist binding to channel gating in alpha7 nicotinic acetylcholine receptors. J. Neurochem. 103, 725-735.

3. Mutants of loop 5 and beta-strand beta6' (Criado, M., Mulet, J., Castillo, M., Aldea, M., Sala, S., Sala, F. (2008) Interactions between loop 5 and beta-strand beta6’ are involved in alpha7 nicotinic acetylcholine receptors channel gating. J. Neurochem. 104, 719-730)

4. Mutants of the cytoplasmic region between M3 and M4 (Castelán, F., et al. (2007) Cytoplasmic regions adjacent to the M3 and M4 transmembrane segments influence expression and function of alpha7 nicotinic acetylcholine receptors. A study with single amino acid mutants. J. Neurochem. 100, 406-415. 96. Criado, M.,et al. (2011) A small cytoplasmic region adjacent to the fourth transmembrane segment of the alpha7 nicotinic receptor is essential for its biogenesis. FEBS Lett. 585, 2477-2480.)

5. Mutants of the N-terminal region (Castillo, M., et al.(2009) Role of the N-terminal alpha-helix in biogenesis of alpha7 nicotinic receptors. J. Neurochem. 108, 1399-1409. 92. Criado, M., et al.(2010) The loop between beta-strands beta2 and beta3 and its interaction with the N-terminal alpha-helix is essential for biogenesis of alpha7 nicotinic receptors. J. Neurochem. 112, 103-111).
6. Mutants of loop 9 (Criado, M., et al. (2010) Role of loop 9 on the function of neuronal nicotinic receptors. Biochim. Biophys. Acta Biomembranes 1798, 654-659).

7. Mutants of the pore domain (Criado, M., et al. (2011) Substitutions of amino acids in the pore domain of homomeric alpha7 nicotinic receptors for analogous residues present in heteromeric receptors modify gating, rectification and binding properties. J. Neurochem. 119, 40-49)

8. Mutants of the beta strand beta3 and the loop B (Criado, M., et al. (2011) Mutants of beta-strand beta3 and the loop B in the interface between alpha7 subunits of a homomeric acetylcholine receptor show functional and pharmacological alterations. J. Neurochem. 118, 968-978).
Antibodies
1. Sigma Aldrich Cat. no. AV35418 Anti-CHRNA7 (AB1) antibody produced in rabbit. WEB

2. Sigma Aldrich Cat. no. N8158 Monoclonal Anti-Nicotinic Acetylcholine Receptor (a7 Subunit) antibody produced in rat.WEB
Diseases
Potential therapeutic target in neurodegenerative, neuropsychiatric and inflammatory disorders: Haydar SN, Dunlop J (2010) Neuronal nicotinic acetylcholine receptors: targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer’s disease. Curr Top Med Chem 10, 144 –152.
Schizophrenia: Freedman R, et al. (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A 94:587–592
Alzheimer: Qi XL, et al. (2007) The consequences of reducing expression of the alpha7 nicotinic receptor by RNA interference and of stimulating its activity with an alpha7 agonist in SH-SY5Y cells indicate that this receptor plays a neuroprotective role in connection with the pathogenesis of Alzheimer’s disease. Neurochem Int 51, 377–383.
Inflammation: Bencherif, M. et al. (2011) Alpha7 nicotinic receptors as novel therapeutic targets for inflammation- based diseases.Cell Mol Life Sci. 68, 931-949.

 

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