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Effects of Cyclothiazide on Glur1 AMPA Receptors

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Effects of Cyclothiazide on Glur1 AMPA Receptors Effects of cyclothiazide on GluR1͞AMPA receptors Sergio Fucile*†, Ricardo Miledi†‡, and Fabrizio Eusebi*§ *Istituto Pasteur–Fondazione Cenci Bolognetti, Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Universita’ di Roma ‘‘La Sapienza,’’ Piazzale Aldo Moro 5, I00185 Rome, Italy; ‡Laboratory of Cellular and Molecular Neurobiology, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550; and §Neuromed Instituto di Ricovero e Cura a Carattere Scientifico, Via Atinese 18, I86077 Isernia, Italy Contributed by Ricardo Miledi, December 22, 2005 Cyclothiazide (CTZ), a positive allosteric modulator of ionotropic Results and Discussion ␣ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)- Concentration–Response Relationships on CTZ Administration. HEK type glutamate receptors, is used frequently to block the desen- 293 cells expressing the rat flip GluR1 subunit (GluR1-HEK sitization of both native and heterologously expressed AMPA cells) responded to AMPA with an inward current that decayed receptors. Specifically, CTZ is known to produce a fast inhibition of biphasically due to a rapid desensitization leading to a fairly AMPA receptor desensitization and a much slower potentiation of stable phase (Fig. 1A). The same cells treated with CTZ gen- the AMPA current. By using patch-clamp techniques, the effects erated AMPA current responses in which the profiles depended of CTZ were studied in HEK 293 cells stably transfected with the rat on the concentrations of AMPA and CTZ, as well as on the flip GluR1 subunit. Upon CTZ treatment, we found an increased duration of the exposure to CTZ. The AMPA currents were apparent affinity for the agonist, a slow whole-cell current poten- greatly potentiated by CTZ in a dose-dependent manner. For tiation, a fast inhibition of desensitization, and a lengthening of instance, by using 150 ␮M AMPA, a 4-s pretreatment of the cells single-channel openings. Furthermore, we show that CTZ alters the with 100 ␮M CTZ increased the peak AMPA currents by 90-fold channel gating events modifying the relative contribution of (EC50 ϭ 28 ␮M; nH ϭ 2.8; n ϭ 5), the currents at the end of ␥ different single-channel classes of conductance ( ), increasing and AMPA application by 636-fold (EC50 ϭ 46 ␮M; nH ϭ 3.6), and ␥ ␥ decreasing, respectively, the contributions of M (medium) and L the current integrals by 730-fold (EC50 ϭ 41 ␮M; nH ϭ 4.5) (Fig. (low) without altering that of the ␥H (high) conductance channels. 1 A and B). The potentiation induced by CTZ was accompanied We also present a kinetic model that predicts well all of the by an increase in the apparent affinity of the receptors for experimental findings of CTZ action. Finally, we suggest a protocol AMPA. For example, in the absence of CTZ, the AMPA NEUROSCIENCE for standard cell treatment with CTZ to attain maximal efficacy of dose͞current–response curve exhibited an EC50 value of 139 ␮M CTZ on GluR1 receptors. (Fig. 2 A and C). In contrast, with 50 ␮M CTZ in the bathing medium (i.e., EC50 value for CTZ with AMPA at 10 ␮M; data glutamate receptor ͉ Hek 293 ͉ receptor potentiation not shown), the AMPA dose͞current–response relation shifted to the left with an Ϸ8-fold decrease in the EC50 value (Fig. 2 B yclothiazide (CTZ) is one of the most potent benzothiadia- and C). To maximize the effects of CTZ, the subsequent ␮ Czides, a class of positive allosteric modulators of non- experiments were done with CTZ at 100 M. NMDA-type glutamate receptors (1, 2), that inhibit receptor desensitization with a marked selectivity for the flip splice AMPA Current Potentiation as a Function of the Duration of CTZ variants (3) of ␣-amino-3-hydroxy-5-methylisoxazole-4- Pretreatment. CTZ potentiated the AMPA current with increas- propionic acid (AMPA) receptors (4). For that reason, treating ing efficacy as the duration of CTZ preincubation was increased. cells with CTZ has become a very useful and widespread tool for Therefore, two different protocols were used to determine the investigating the molecular composition of AMPA receptors and dependence of the AMPA current potentiation on the CTZ pretreatment. One protocol consisted of applying AMPA (150 the mechanisms of desensitization (for review, see ref. 5). ␮ The AMPA receptors (for review, see ref. 6) are homo- or M) for 10 s before adding the CTZ (Fig. 3A). Under these heterotetrameric assemblies (7) organized in dimer pairs (8, 9), conditions, CTZ potentiated the AMPA current, and the cor- responding rising phase was best fitted to a single exponential and their rapid desensitization is: (i) controlled by the dimer Ϯ ϭ interface, being reduced by CTZ through dimer interface sta- function with a mean time constant of 16 4s(n 5), indicating bilization (10); (ii) dependent on the receptor subunit compo- that CTZ needed many seconds to maximally potentiate the sition, including alternative splicing (4, 11, 12); and (iii) char- AMPA currents. When AMPA and CTZ were applied simulta- acterized by the receptor entry into an inactive state displaying neously (Fig. 3 A Right), the current rise did not change an increased binding affinity (13). significantly, indicating that the desensitization induced by Together with a fast inhibition of desensitization (4, 14–16), AMPA developed faster than the potentiating action of CTZ. Another protocol consisted in monitoring the GluR1 potentia- CTZ causes many other effects on AMPA-type receptors in- tion by making brief applications of AMPA (150 ␮M) during a cluding: (i) a slow increase in the peak amplitude of whole-cell continuous application of CTZ (Fig. 3B). Although the current currents (2, 4, 14); (ii) an enhancement of the current deacti- took many seconds to reach the maximal amplitude (4.8 Ϯ 0.6-s vation time (14); (iii) a lengthening of single-channel openings time constant; n ϭ 5; Fig. 3C), the inhibition of desensitization (2); (iv) a decrease in agonist binding (17, 18); and (v) an increase was much faster (Fig. 3D). Both, current potentiation and in the apparent affinity for agonists (2, 4, 14). inhibition of desensitization exhibited a slower recovery than Several studies have provided important insights into the their onset (Fig. 3 C and D). Taken together, these findings structural determinants and mechanisms of the interaction of indicate that the interaction between GluR1 and CTZ develops CTZ with AMPA receptors (10, 15, 19–22). Because those studies have been made in different systems, however, a global picture of the various effects of CTZ is still lacking. This study Conflict of interest statement: No conflicts declared. reports some of the effects of CTZ on AMPA receptors, all in Abbreviations: CTZ, cyclothiazide; AMPA, ␣-amino-3-hydroxy-5-methylisoxazole-4-propi- the same cell system (HEK 293 cells stably transfected with the onic acid. rat GluR1 subunit), highlighting the discrepancy between the †To whom correspondence may be addressed. E-mail: [email protected] or fast inhibition of current desensitization and the slow current [email protected]. potentiation. © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0511063103 PNAS ͉ February 21, 2006 ͉ vol. 103 ͉ no. 8 ͉ 2943–2947 Downloaded by guest on September 27, 2021 Fig. 1. Effects of CTZ on whole-cell currents elicited by AMPA. (A) Typical whole-cell currents elicited in a cell by AMPA (solid bars) alone or in the presence of CTZ (hatched bars), applied for 4 s before the coapplication of CTZ plus AMPA. For this and the other figures, the holding potential was Ϫ70 mV. (B) The CTZ dose͞current–response relationship to AMPA (150 ␮M). Data (n ϭ 6) represent current amplitudes at peak (F) and at the end of AMPA application (E) and current integrals () normalized to the values obtained without CTZ (mean peak current, 82 Ϯ 20 pA; mean current at the end of AMPA application, 9 Ϯ 3 pA; mean current integral, 40 Ϯ 18 pC) and fitted to Hill equations. The resulting EC50 and nH values were 28, 46, and 48 ␮M, and 2.8, 3.6, and 4.5, respectively. Fig. 2. Effects of CTZ on the AMPA dose͞current–response relationship. very quickly, leading to a prompt block of desensitization Typical whole-cell currents induced in two different cells by AMPA alone (A) followed by a delayed current potentiation. or by AMPA plus CTZ (different cell from A)(B). (C) AMPA dose͞peak current response to AMPA alone (F) or in the presence of 50 ␮M CTZ (E). Imax ϭϪ524 Ϯ ϭϪ Ϯ ϭ CTZ Modulation of GluR1 Single-Channel Activity. To investigate 184 pA (control); I 5.8 1.1 nA with CTZ (n 5). In the control, EC50 and ␮ further the mechanisms underlying the modulation of AMPA nH values were 139 M and 2.65, respectively. With CTZ at the indicated concentration, EC and n values were 18 ␮M and 1.27, respectively. currents by CTZ, an analysis was made of the single-channel 50 H characteristics of AMPA-activated GluR1 receptors by using the patch-clamp outside-out recording mode. When patch mem- system, multiple effects of CTZ on homomeric GluR1 AMPA branes were exposed to AMPA (1 ␮M), there was an immediate receptors. Some of these effects have been described for differ- activation of channel openings, with a mean frequency Ϸ10 Hz ent AMPA receptor subtypes in native and heterologous systems (e.g., Fig. 4A; n ϭ 4). Analyses of unitary events disclosed three (2, 4, 14–16; for review, see ref. 5). Thus, CTZ modulates classes of current levels in each patch, with no obvious transitions whole-cell AMPA currents, producing: (i) a block of desensiti- between the different conductance levels. The three classes of zation, (ii) a delayed potentiation of current amplitude, (iii) and ␥ Ϯ channel conductance were: a low, L, at 10.9 0.3 pS; a medium, an increase of agonist affinity.
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