|
|
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4
2 Acetylcholine Receptors
Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania
Human neuronal nicotinic acetylcholine receptor (AChR)
4 subunits and an
4 mutant (S247F
4) found in autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) were expressed along with
2 in permanently transfected tsA201 human embryonic kidney cell lines. Their sensitivity to activation, desensitization, and up-regulation by cholinergic ligands was investigated. Up-regulation after 3 to 24 h resulted primarily from an increase in assembly of AChRs from large pools of unassembled subunits, but up-regulation also resulted from a 5-fold increase in the lifetime of AChRs in the surface membrane. Up-regulation does not require current flow through surface membrane AChRs, because up-regulation occurs in the presence of the channel blocker mecamylamine and with the
4 mutant, which prevents nearly all AChR function. Both membrane-permeable ligands like nicotine and much less permeable quaternary amine cholinergic ligands can act as pharmacological chaperones within the endoplasmatic reticulum to promote the assembly of AChRs. Agonists are more potent pharmacological chaperones than antagonists, presumably because activated or desensitized conformations assemble more efficiently. Assembly intermediates are disrupted by solubilization in Triton X-100, but chemical cross-linking stabilizes a putative assembly intermediate approximately the size of an
4
2
4
2 tetramer.
Address correspondence to: Dr. Jon Lindstrom, Department of Neuroscience, University of Pennsylvania Medical School, 217 Stemmler Hall 36th and Hamilton Walk, Philadelphia, PA 19104. E-mail: jslkk{at}mail.med.upenn.edu
This article has been cited by other articles:
![]() |
X. W. Fu, J. Lindstrom, and E. R. Spindel Nicotine Activates and Up-Regulates Nicotinic Acetylcholine Receptors in Bronchial Epithelial Cells Am. J. Respir. Cell Mol. Biol., July 1, 2009; 41(1): 93 - 99. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. D. Son, F. J. Moss, B. N. Cohen, and H. A. Lester Nicotine Normalizes Intracellular Subunit Stoichiometry of Nicotinic Receptors Carrying Mutations Linked to Autosomal Dominant Nocturnal Frontal Lobe Epilepsy Mol. Pharmacol., May 1, 2009; 75(5): 1137 - 1148. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Liu, A. M. McGlinn, A. Fernandes, A. H. Milam, C. E. Strang, M. E. Andison, J. M. Lindstrom, K. T. Keyser, and R. A. Stone Nicotinic Acetylcholine Receptor Subunits in Rhesus Monkey Retina Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1408 - 1415. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. V. Kenny, S. L. Cousins, L. Pinho, and F. A. Stephenson The Integrity of the Glycine Co-agonist Binding Site of N-Methyl-D-aspartate Receptors Is a Functional Quality Control Checkpoint for Cell Surface Delivery J. Biol. Chem., January 2, 2009; 284(1): 324 - 333. [Abstract] [Full Text] [PDF] |
||||
![]() |
X. A. Perez, T. Bordia, J. M. McIntosh, S. R. Grady, and M. Quik Long-Term Nicotine Treatment Differentially Regulates Striatal {alpha}6{alpha}4{beta}2* and {alpha}6(Non{alpha}4){beta}2* nAChR Expression and Function Mol. Pharmacol., September 1, 2008; 74(3): 844 - 853. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Moroni, R. Vijayan, A. Carbone, R. Zwart, P. C. Biggin, and I. Bermudez Non-Agonist-Binding Subunit Interfaces Confer Distinct Functional Signatures to the Alternate Stoichiometries of the {alpha}4{beta}2 Nicotinic Receptor: An {alpha}4-{alpha}4 Interface Is Required for Zn2+ Potentiation J. Neurosci., July 2, 2008; 28(27): 6884 - 6894. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. Lindstrom 'Seronegative' myasthenia gravis is no longer seronegative Brain, July 1, 2008; 131(7): 1684 - 1685. [Full Text] [PDF] |
||||
![]() |
A. Kuryatov, J. Onksen, and J. Lindstrom Roles of Accessory Subunits in {alpha}4{beta}2* Nicotinic Receptors Mol. Pharmacol., July 1, 2008; 74(1): 132 - 143. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Song, H. S. Sekhon, X. W. Fu, M. Maier, Y. Jia, J. Duan, B. J. Proskosil, C. Gravett, J. Lindstrom, G. P. Mark, et al. Activated Cholinergic Signaling Provides a Target in Squamous Cell Lung Carcinoma Cancer Res., June 15, 2008; 68(12): 4693 - 4700. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. Kabbani, M. P. Woll, R. Levenson, J. M. Lindstrom, and J.-P. Changeux Intracellular complexes of the 2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics PNAS, December 18, 2007; 104(51): 20570 - 20575. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. Rezvani, Y. Teng, D. Shim, and M. De Biasi Nicotine Regulates Multiple Synaptic Proteins by Inhibiting Proteasomal Activity J. Neurosci., September 26, 2007; 27(39): 10508 - 10519. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Teper, D. Whyte, E. Cahir, H. A. Lester, S. R. Grady, M. J. Marks, B. N. Cohen, C. Fonck, T. McClure-Begley, J. M. McIntosh, et al. Nicotine-Induced Dystonic Arousal Complex in a Mouse Line Harboring a Human Autosomal-Dominant Nocturnal Frontal Lobe Epilepsy Mutation J. Neurosci., September 19, 2007; 27(38): 10128 - 10142. [Abstract] [Full Text] [PDF] |
||||
![]() |
R. Nashmi, C. Xiao, P. Deshpande, S. McKinney, S. R. Grady, P. Whiteaker, Q. Huang, T. McClure-Begley, J. M. Lindstrom, C. Labarca, et al. Chronic Nicotine Cell Specifically Upregulates Functional {alpha}4* Nicotinic Receptors: Basis for Both Tolerance in Midbrain and Enhanced Long-Term Potentiation in Perforant Path J. Neurosci., August 1, 2007; 27(31): 8202 - 8218. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. C. Perry, D. Mao, A. B. Gold, J. M. McIntosh, J. C. Pezzullo, and K. J. Kellar Chronic Nicotine Differentially Regulates {alpha}6- and beta3-Containing Nicotinic Cholinergic Receptors in Rat Brain J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 306 - 315. [Abstract] [Full Text] [PDF] |
||||
![]() |
L. Tapia, A. Kuryatov, and J. Lindstrom Ca2+ Permeability of the ({alpha}4)3(beta2)2 Stoichiometry Greatly Exceeds That of ({alpha}4)2(beta2)3 Human Acetylcholine Receptors Mol. Pharmacol., March 1, 2007; 71(3): 769 - 776. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. S. McGehee Nicotinic and Opioid Receptor Interactions in Nicotine Addiction Mol. Interv., December 1, 2006; 6(6): 311 - 314. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Kishi and J. H. Steinbach Role of the Agonist Binding Site in Up-Regulation of Neuronal Nicotinic {alpha}4beta2 Receptors Mol. Pharmacol., December 1, 2006; 70(6): 2037 - 2044. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Tumkosit, A. Kuryatov, J. Luo, and J. Lindstrom beta3 Subunits Promote Expression and Nicotine-Induced Up-Regulation of Human Nicotinic {alpha}6* Nicotinic Acetylcholine Receptors Expressed in Transfected Cell Lines Mol. Pharmacol., October 1, 2006; 70(4): 1358 - 1368. [Abstract] [Full Text] [PDF] |
||||
![]() |
Y. Xiao, H. Fan, J. L. Musachio, Z.-L. Wei, S. K. Chellappan, A. P. Kozikowski, and K. J. Kellar Sazetidine-A, A Novel Ligand That Desensitizes {alpha}4beta2 Nicotinic Acetylcholine Receptors without Activating Them Mol. Pharmacol., October 1, 2006; 70(4): 1454 - 1460. [Abstract] [Full Text] [PDF] |
||||
![]() |
F. Picard, D. Bruel, D. Servent, W. Saba, C. Fruchart-Gaillard, M.-A. Schollhorn-Peyronneau, D. Roumenov, E. Brodtkorb, S. Zuberi, A. Gambardella, et al. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study Brain, August 1, 2006; 129(8): 2047 - 2060. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Moroni, R. Zwart, E. Sher, B. K. Cassels, and I. Bermudez {alpha}4beta2 Nicotinic Receptors with High and Low Acetylcholine Sensitivity: Pharmacology, Stoichiometry, and Sensitivity to Long-Term Exposure to Nicotine Mol. Pharmacol., August 1, 2006; 70(2): 755 - 768. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. E. McCallum, N. Parameswaran, T. Bordia, H. Fan, J. M. McIntosh, and M. Quik Differential Regulation of Mesolimbic {alpha}3/{alpha}6beta2 and {alpha}4beta2 Nicotinic Acetylcholine Receptor Sites and Function after Long-Term Oral Nicotine to Monkeys J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 381 - 388. [Abstract] [Full Text] [PDF] |
||||