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	Figure 1. GIRK activation by mGluR2. (A) Two-electrode voltage-clamp recording from a cell expressing mGluR2 and GIRK1. Bars above trace show solutions applied. (B) Current-voltage relationships of the GIRK currents at the times indicated by arrows in A: in hK alone (1) and in glutamate (2). Each net GIRK1 I-V curve was obtained by subtraction of the I-V curve recorded after addition of Ba2+. (C) Gluta-mate dose-response curve, with apparent Kd = 0.63 μM, fitted to the standard Michaelis-Menten equation. n = 3 or 4 cells for each glutamate concentration. (D) A cell-attached patch clamp record of the activity of the GIRK channel with 10 μM K-glutamate in the pipette, from an oocyte injected with RNAs of GIRK1 and mGluR2.
	Figure 2. Inhibition of GIRK by mGluR1a. (A) Two-electrode voltage-clamp recording from a single cell injected with RNAs of GIRK1 (500 pg) and mGluR1a (25 pg). ND, stands for ND96. (B) Average recording from cells of one donor exposed to glutamate (•, n = 4) and unexposed to glutamate (○, n = 6). Ba2+ was not applied, and current was expressed as percent of the current in hK solution (IhK + In); I = 0 in ND96. (C) Inhibition of GIRK channel activity by mGluR1a in EGTA-treated oocytes: comparison of cells exposed to glutamate (n = 4) to cells unexposed to glutamate (n = 4). The cells were from the same donor, injected with 25 pg mGluR1a RNA and 500 pg GIRK1 RNA. The ND96 solution was changed to the hK solution at time t = 0. Currents in each oocyte were normalized to the peak basal GIRK current, IhK. Average traces from all 4 oocytes are shown. The mean IhK was 313 ± 29 nA (n = 8) in these oocytes. (D) Current-voltage relationships of GIRK currents at the times indicated by arrows in C, in a cell injected with EGTA: in hK (1) and in glutamate after the decay of the current (2). Net GIRK I-V curves were obtained as in Fig. 1 B. (E) Inhibition of GIRK1/GIRK2 channel activity by mGluR1a in EGTA-treated oocytes. Presentation as in C; n = 4 oocytes for each treatment. In this batch, oocytes were injected with 50 pg mGluR1a RNA and 250 pg of each of the GIRK1 and GIRK2 RNAs. Average IhK was 4,126 ± 707 nA (n = 8). (F) Absence of glutamate-activated inward current in oocytes incubated in 300 μM BaCl2. Oocytes were injected with RNAs of mGluR1a (25 pg) and GIRK1 (500 pg) and treated with EGTA. Ba2+ (300 μM) was added to all solutions. Currents in each cell were normalized to the peak inward current observed in the hK solution, which, because of the block of GIRK, equals to In (the average current in the hK solution was 86 ± 8 nA, n = 5). (G) Inhibition of m2R-induced activation of GIRK by mGluR1a. Oocytes expressing mGluR1a, m2R, and GIRK1, and injected with EGTA before recording, were placed in hK solution and then exposed to 10 μM ACh, which activated GIRK (the record starts at the time of addition of ACh). This current is denoted IACh. 3 min after exposure to ACh (at the time indicated by the arrow), one group of cells was exposed to glutamate (•, n = 3), which caused a decrease in the current compared with cells that were not exposed to glutamate (○, n = 3). The current is expressed as percent of IACh; records averaged from all oocytes in each group are shown.
	Figure 5. mGluR1a-induced inhibition of GIRK is blocked by PKC inhibitors and mimicked by PMA. Oocytes expressing mGluR1a (30 or 50 pg/ oocyte), GIRK1 and GIRK2 (250 or 500 pg/oocyte) were injected with EGTA before recording (except in F). In A, B, D and E, the treatments are presented as follows: empty bars, no treatment (vehicle only); shaded bars, BIS; black bars, staurosporine. (A) Staurosporine and BIS do not significantly alter the amplitude of IhK. Summary of two oocyte batches, n = 8 for each treatment. In each oocyte, IhK was normalized to the average IhK amplitude in untreated cells of the same oocyte batch. (B) Staurosporine and BIS attenuate the basal desensitization of IhK. Same oocytes as in A. In each oocyte, the extent of desensitization was calculated as [1 − (IhK at the end of the 8 min exposure to hK)/ (peak IhK)] × 100%. (C) Gluta-mate (trace denoted: + gluta-mate) fails to cause inhibition of GIRK in a representative cell treated with staurosporine; the activation of GIRK remains unimpaired. For comparison, a re-cord is shown from an oocyte (from the same donor) treated with staurosporine but not exposed to glutamate (no gluta-mate). (D) The mGluR1a- induced inhibition of IhK is suppressed by BIS and staurosporine: a summary of two experiments. Same oocytes batches as in A and B. The extent of IhK inhibition was calculated as explained in Fig. 3 C. (E) mGluR1a-induced GIRK activation is not significantly changed by BIS and staurosporine. (F) PMA inhibits the basal GIRK current. Oocytes were incubated in ND96 as usual and, at t = 0, exposed either to the normal hK solution (no PMA; n = 5) or to hK containing 10 nM PMA (+ PMA; n = 5). Records averaged from all oocytes in each group are shown.
	Figure 3. PTX suppresses mGluR1a-induced activation of GIRK but has little effect on mGluR1a-induced GIRK inhibition. (A) Inhibition of GIRK1/ GIRK2 channel activity by mGluR1a in EGTA-injected oocytes treated with PTX: comparison of cells exposed to glutamate (n = 4) to cells unexposed to glutamate (n = 4). The cells were injected with RNAs of mGluR1a (50 pg), GIRK1 (250 pg), and GIRK2 (250 pg). The ND96 solution was changed to the hK solution at time t = 0. Currents in each oocyte were normalized to the peak basal GIRK current, IhK. Records averaged from all oocytes in each group (n = 4) are shown. Average IhK was 833 ± 193 nA (n = 8) in these oocytes, and 1,993 ± 331 nA (n = 8) in PTX-untreated oocytes of the same donor. (B) The effect of PTX treatment on basal (IhK) and glutamate-evoked (Iglu) GIRK1/GIRK2 currents: a summary from oocytes of two donors (n = 8 in each group). IhK or Iglu in each cell was expressed as percent of control (i.e., average IhK or Iglu in the untreated group of oocytes of the same donor), and the results were averaged across all cells. Asterisks denote statistically significant differences, P < 0.05 or better. (C) The effect of PTX treatment on mGluR1a-induced GIRK1/GIRK2 inhibition. Same two oocyte batches as in B. The extent of glutamate-evoked inhibition was calculated as follows: first, in each cell, the current at the end of the record (t = 8 min in the hK solution) was expressed as percent of IhK measured at t = 2 min. In glutamate-exposed oocytes, this value was normalized to the average current in cells unexposed to glutamate at t = 8 min. This normalization procedure allowed averaging of the results despite the large difference in the absolute amplitudes of the currents recorded in oocytes of different donors.

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