Role of the outer beta-sheet in divalent cation modulation of alpha7 nicotinic receptors

Molecular Pharmacology
James T McLaughlinRobert L Rosenberg

Abstract

alpha-7 Nicotinic acetylcholine receptors (AChRs) exhibit a positive modulation by divalent cations similar to that observed in other AChRs. In the chick alpha7 AChR, this modulation involves a conserved glutamate in loop 9 (Glu172) that undergoes agonist-dependent movements during activation. From these observations, we hypothesized that movements of the nearby beta-sheet formed by the beta7, beta9, and beta10 strands may be involved in agonist activation and/or divalent modulation. To test this hypothesis, we examined functional properties of cysteine mutations of the beta7 and beta10 strands, alone or in pairs. We postulated that reduced flexibility or mobility of the beta7/beta9/beta10-sheet as a result of introduction of a disulfide bond between the beta strands would alter activation by agonists. Using a nondesensitizing alpha7 mutant background (L247T), we identified one mutant pair, K144C + T198C, that exhibited a unique characteristic: it was fully activated by divalent cations (Ca2+, Ba2+, or Sr2+) in the absence of acetylcholine (ACh). Divalent-evoked currents were blocked by the alpha7 antagonist methyllycaconitine and were abolished when Glu172 was mutated to glutamine. When the K144C + T198C pair was expressed in ...Continue Reading

References

Jan 1, 1996·Neuropharmacology·M HolmgrenG Yellen
Jul 9, 1998·Methods : a Companion to Methods in Enzymology·H K FeirabendS Ploeger
Feb 12, 2002·Nature Reviews. Neuroscience·Arthur Karlin
Feb 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nicolas Le NovèreJean-Pierre Changeux
Mar 7, 2002·American Journal of Physiology. Cell Physiology·Donnie EddinsRobert L Rosenberg
Oct 10, 2002·American Journal of Physiology. Cell Physiology·Donnie EddinsRobert L Rosenberg
Oct 17, 2002·The Journal of Biological Chemistry·Paul A DaviesEwen F Kirkness
Nov 19, 2002·Journal of Neurobiology·Steven M Sine
Jun 27, 2003·Nature·Atsuo MiyazawaNigel Unwin
May 29, 2004·Trends in Neurosciences·Henry A LesterDennis A Dougherty
Feb 11, 2005·Journal of Molecular Biology·Nigel Unwin
Apr 29, 2005·Proceedings of the National Academy of Sciences of the United States of America·Richard J LawJ Andrew McCammon
Jun 16, 2005·The Journal of General Physiology·Nuriya MukhtasimovaSteven M Sine
Oct 12, 2005·The Journal of Biological Chemistry·Xinan XiuDennis A Dougherty
Nov 11, 2005·Nature·Cynthia Czajkowski

❮ Previous
Next ❯

Citations

Sep 2, 2008·Proceedings of the National Academy of Sciences of the United States of America·Srinivasan P Venkatachalan, Cynthia Czajkowski
May 30, 2008·Frontiers in Bioscience : a Journal and Virtual Library·Gregg B Wells
Aug 5, 2008·Neuropharmacology·Andrew J Thompson, Sarah C R Lummis
Apr 28, 2006·Molecular Pharmacology·Jon Lindstrom
Feb 28, 2007·Molecular Pharmacology·James T McLaughlinRobert L Rosenberg
Sep 23, 2008·Nature Structural & Molecular Biology·Paul S MillerTrevor G Smart
May 1, 2009·Chembiochem : a European Journal of Chemical Biology·Kristin R GleitsmanDennis A Dougherty
Jul 24, 2020·The Journal of General Physiology·Kathiresan NatarajanSteven M Sine
Sep 2, 2009·Nature Reviews. Drug Discovery·Antoine TalyJean-Pierre Changeux
Jan 26, 2010·Trends in Pharmacological Sciences·Paul S Miller, Trevor G Smart

❮ Previous
Next ❯

Related Concepts

Related Feeds

Basal Forebrain- Circuits

Basal forebrain is a region in the brain important for production of acetylcholine and is the major cholinergic output of the CNS. Discover the latest research on circuits in the basal forebrain here.