On the Mechanism of Desensitization in Quisqualate-Type Glutamate Channels

Abstract

Desensitization of crayfish glutamate channels was studied in outside-out patches employing an improved fast drug-application technique. Low concentrations of glutamate produced substantial desensitization without correlation with the detected number of open channels. The desensitization time constant (tau(D)) was found to be independent of glutamate concentration (0.3-20 mM). These results suggest that in addition to desensitization from a state of fully liganded channels, a substantial fraction of desensitization occurs also from channels in a partly-liganded state. A kinetic model was developed. The model accounts for the multifaceted behavior of desensitization as well as for resensitization.

Long-Term Potentiation Alters the Modulator Pharmacology of AMPA-Type Glutamate Receptors

“…Previous simulations have shown that an AMPA receptor model with two independent binding sites better fits responses following application of high-affinity glutamate agonists than models incorporating additional binding sites (Clements et al 1998). Thus the present simulation follows Tour et al (2000) in simplifying the AMPA receptor model to consist of one and two ligand bound states (RL 1 and RL 2 ) with the latter leading to an open state (RL 2 open). Desensitization, which is unusually rapid for AMPA receptors, occurs in the model from RL 1 , RL 2 , and RL 2 open, as illustrated in Fig.…”

“…Simulations of the interaction between the effects of LTP and CTZ were carried out using a variant of previous kinetic models of the AMPA receptor (Ambros-Ingerson and Lynch 1993;Clements et al 1998;Tour et al 2000). Figure 1 depicts the states used in the current model and the associated rate constants linking the states.…”

“…Various arguments suggest that each of the homologous subunits in the AMPA receptor possesses a binding site for glutamate, raising the possibility that the behavior of the receptor will depend on the number of agonist molecules it binds during a given release event. Experimental work indicates that at least two binding events are required to open the channel (Clements et al 1998;Tour et al 2000), and it has been proposed that distinct conductance states are associated with the number of bound molecules (Rosenmund et al 1998). Previous simulations have shown that an AMPA receptor model with two independent binding sites better fits responses following application of high-affinity glutamate agonists than models incorporating additional binding sites (Clements et al 1998).…”

“…1A. The idea of desensitization proceeding from both a closed and an open state of the receptor is based on evidence regarding the kinetics of desensitization at various glutamate concentrations (Tour et al 2000;Trussell and Fischbach 1989). Figure 1B lists the values of the rate constants used in the simulations reported here, while (Werling et al 1983)].…”

Furthering pharmacological and physiological assessment of the glutamatergic receptors at the Drosophila neuromuscular junction

“…Possible kainate could act on the receptor to desensitize it to glutamate or in addition act as a non-competitive antagonist. Quisqualate receptors are known to be prone to desensitization at the crayfish NMJ (Tour et al, 2000) as well as other glutamate receptors (Sun et al, 2002).…”