RT Journal Article
SR Electronic
T1 Mechanisms of Modal Activation of GluA3 Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.111.071688
DO 10.1124/mol.111.071688
A1 Kinning Poon
A1 Ahmed H. Ahmed
A1 Linda M. Nowak
A1 Robert E. Oswald
YR 2011
UL http://molpharm.aspetjournals.org/content/early/2011/04/04/mol.111.071688.abstract
AB AMPA receptors are the major excitatory neurotransmitter receptors in the CNS and are involved in numerous neurological disorders. An agonist-binding site is present in each of four subunits that form a functional channel. Binding consists of three steps: docking of agonist to the bi-lobed ligand binding domain (LBD), closure of the LBD, and increased stability of the closed-lobe conformation through interlobe hydrogen bonding. We describe GluA3 single channel currents activated by nitrowillardiine (NO2W) and chlorowillardiine (ClW) in the presence of cyclothiazide, in conjunction with crystal structures of GluA2 and GluA3 LBDs bound to fluorowillardiine (FW), ClW, and NO2W. When bound to NO2W or ClW, the GluA3 channel opens to three conductance levels with comparable open probabilities and displays modal behavior similar to that obtained with glutamate and FW as agonists (Poon et al., 2010). At lower concentrations, ClW evoked an alternate kinetic behavior, consisting of high open probability in lower conductance states. The structure of ClW bound to GluA3 LBD exhibits a unique partially open hydrogen bonding structure that may be associated with these alternative kinetics. NO2W evoked longer open times than seen for other agonists in high and very high modes. The structure of GluA2 LBD bound to NO2W exhibits fully closed lobes with additional interlobe interactions mediated by the nitro group. Beyond differences in efficacy between full and partial agonists, the complexities of the single channel behavior of AMPA receptors may also be associated with small interactions that modify the stability of various degrees of closure.