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Biophys J, April 2000, p. 1786-1803, Vol. 78, No. 4

Chloride Channels of Glycine and GABA Receptors with Blockers: Monte Carlo Minimization and Structure-Activity Relationships

Boris S. Zhorov*dagger and Piotr D. Bregestovski*

 *INSERM U-261 Neurobiologie Cellulaire, Institut Pasteur, Paris, France; and  dagger Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia

GABA and glycine receptors (GlyRs) are pentameric ligand-gated ion channels that respond to the inhibitory neurotransmitters by opening a chloride-selective central pore lined with five M2 segments homologous to those of alpha 1 GlyR/ ARVG2'LGIT6'TVLTMTTQSSGSR. The activity of cyanotriphenylborate (CTB) and picrotoxinin (PTX), the best-studied blockers of the Cl- pores, depends essentially on the subunit composition of the receptors, in particular, on residues in positions 2' and 6' that form the pore-facing rings R2' and R6'. Thus, CTB blocks alpha 1 and alpha 1/beta , but not alpha 2 GlyRs (Rundström, N., V. Schmieden, H. Betz, J. Bormann, and D. Langosch. 1994. Proc. Natl. Acad. Sci. U.S.A. 91:8950-8954). PTX blocks homomeric receptors (alpha 1 GlyR and rat rho 1 GABAR), but weakly antagonizes heteromeric receptors (alpha 1/beta GlyR and rho 1/rho 2 GABAR) (Pribilla, I., T. Takagi, D. Langosch, J. Bormann, and H. Betz. 1992. EMBO J. 11:4305-4311; Zhang D., Z. H. Pan, X. Zhang, A. D. Brideau, and S. A. Lipton. 1995. Proc. Natl. Acad. Sci. U.S.A. 92:11756-11760). Using as a template the kinked-helices model of the nicotinic acetylcholine receptor in the open state (Tikhonov, D. B., and B. S. Zhorov. 1998. Biophys. J. 74:242-255), we have built homology models of GlyRs and GABARs and calculated Monte Carlo-minimized energy profiles for the blockers pulled through the pore. The profiles have shallow minima at the wide extracellular half of the pore, a barrier at ring R6', and a deep minimum between rings R6' and R2' where the blockers interact with five M2s simultaneously. The star-like CTB swings necessarily on its way through ring R6' and its activity inversely correlates with the barrier at R6': Thr6's and Ala2's in alpha 2 GlyR confine the swinging by increasing the barrier, while Gly2's in alpha 1 GlyR and Phe6's in beta  GlyR shrink the barrier. PTX has an egg-like shape with an isopropenyl group at the elongated end and the rounded end trimmed by ether and carbonyl oxygens. In the optimal binding mode to alpha 1 GlyR and rho 1 GABAR, the rounded end of PTX accepts several H-bonds from Thr6's, while the elongated end enters ring R2'. The lack of H-bond donors on the side chains of Phe6's (beta  GlyR) and Met6's (rho 2 GABAR) deteriorates the binding. The hydrophilic elongated end of picrotin does not fit the hydrophobic ring of Pro2's/Ala2's in GABARs, but fit a more hydrophilic ring with Gly2's in GlyRs. This analysis provides explanations for structure-activity relationships of noncompetitive agonists and predicts a narrow pore of LGICs in agreement with experimental data on the permeation of organic cations.

Biophys J, April 2000, p. 1786-1803, Vol. 78, No. 4
© 2000 by the Biophysical Society   0006-3495/00/04/1786/18  $2.00


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