Yakubovich D , Berlin S , Kahanovitch U , Rubinstein M , Farhy-Tselnicker I , Styr B , Keren-Raifman T , Dessauer CW , Dascal N .

R01 GM060419 NIGMS NIH HHS

	Fig 4. Measuring the surface density of GIRK1/2 and Gβγ in Xenopus oocytes. (A) Immunochemical estimation of the amount of GIRK1 in manually separated plasma membranes of Xenopus oocytes injected with 1 or 2 ng of GIRK RNA. Shown is a Western blot of 20 manually separated plasma membranes and 4 cytosols, and variable known amounts of the GST-fused distal C-terminus of GIRK1 (the antibody's epitope) used for calibration of the antibody-produced signal. There was a non-specific band at ~75 KDa in cytosols but not PM of uninjected oocytes (“uninj”). (B) Summary of quantitative analysis of GIRK1 in PM from Western blots of 7 separate experiments. The fully glycosylated band was observed in 4 out of 7 blots. Molar amounts of protein and PM densities from Western blots were calculated as detailed in Methods. The dark red bar is the GIRK1/2 surface density in the high-density group estimated from Iβγ (see Table 1), shown for comparison. (C) Examples of confocal images of oocytes expressing YFP-GIRK1/2 (5 ng RNA) and Gβγ-YFP (5 ng RNA). (D) Estimating YFP molecules density in PM using YFP-GIRK1/2 as molecular ruler. A representative experiment is shown. The left plot shows the measured intensities of YFP-GIRK1/2 and YFP-Gβ coexpressed with wt Gγ in a separate group of oocytes (5:1 ng RNA). The right plot shows the PM densities of YFP in the YFP-GIRK1/2 oocytes, calculated as follows: Iβγ was 14.5±2.1 μA (n = 6), corresponding to 11.4±1.6 channels/μm2, or 22.8±3.3 YFP molecules/μm2. The density of YFP in the YFP-Gβγ expressing oocytes was calculated based on relative intensities from the left plot. (E) Estimating the amount of endogenous Gβ and expressed YFP-Gβ or YFP-Gβ-XL (5 ng RNA) coexpressed with wt-Gγ, in manually separated plasma membranes. Protocol was similar to Fig 4A; wt purified recombinant Gβγ was used for calibration. In parallel to biochemical measurements, we also measured GIRK currents and YFP intensity in 5–15 oocytes expressing either YFP-GIRK1/2-Gβγ or YFP-Gβγ, as explained in D. (F) Summary of YFP-Gβγ surface density measurements in 4 experiments by the two methods, quantitative Westerns and confocal imaging with YFP-GIRK1/2 as the molecular ruler. doi:10.1371/journal.pcbi.1004598.g004
	Fig 2. Gating of GIRK1/2 by Gβγ.(A) Sources of Gβγ for GIRK activation. GαGDP●Gβγ is the undissociated G protein heterotrimer. Note that, in isolated Xenopus oocytes or HEK cells, in the absence of added agonist the right, GPCR-dependent branch of the reaction of Fig 2A does not significantly contribute to Ibasal, because there are no known Gαi/o-coupled GPCRs or ambient agonists that can "basally" activate the GTPase cycle (discussed in [51]). (B) The schemes of “concerted”, “graded contribution” and “separate gating transitions” models of channel activation. (C) Graded contribution of the four Gβγ-occupied GIRK states to Po. Fractional Po for each state was calculated by normalizing published Po values [13] of each of the four modes (corresponding to 1–4 Gβγ occupied state) to Po,max (corresponding to 4 Gβγ occupied channel). Almost identical values have been obtained from fractional activation ratios for engineered GIRK channels having 1 to 4 Gβγ binding sites [14].
	Fig 3. Single channel and whole-cell data reveal incomplete activation of GIRK1/2 by agonist compared to Gβγ.(A) Activity of GIRK1/2 in a cell-attached patch of an oocyte expressing the channel, m2R and Gβγ, without an agonist in the pipette. Right panel shows a 2 minutes segment of record, with zoom (below) on a shorter segment. The amplitude distribution histogram of the same 2 min-segment is shown on the right. Red line shows a two-component Gaussian fit. Isingle was determined as the difference between the fitted midpoints (μ) of the GIRK current peak on the right (μ2) and the left peak which corresponds to noise (μ1). (B) Activity of GIRK1/2 channels in a cell-attached patch of an oocyte expressing the channel and m2R and activated by 2 μM ACh present in the patch pipette. (Asterisks denote artifacts produced by capacity discharges of patch clamp headstage). The corresponding amplitude histogram of the 2 min-segment of the record is shown on the right. In A and B, GIRK1/2 was expressed at low densities (GIRK1, 10–50 pg RNA; GIRK2, 7–17 pg RNA) whereas RNAs of m2R (1–2 ng/oocyte) and Gβγ (5:1 ng/oocyte) were chosen to produce saturating concentrations of these proteins. Inward K+ currents are shown as upward deflections from zero level. In the traces shown, acquisition was at 20 KHz with 5 KHz analog filter. Very similar values of Isingle were obtained with 2 KHz filtering (not shown). (C) Single channel currents (left plot) are identical with either ACh or Gβγ. (D) Po is lower with ACh than with Gβγ (p = 0.029). Bars in C and D show mean±SEM, number of patches is shown above the bars. (E) Summary of whole-cell GIRK1/2 currents at three expression levels (densities). See Table 1 for details. (F) Left panel shows the Itotal/Iβγ ratios at three channel densities, calculated from data of Table 1. The right panel shows the fractional open probabilities of channels occupied by 0–4 Gβγ, same as in Fig 2C but in a simple graphic form. The red dotted lines are drawn to allow direct comparison of the experimental data from the left panel with the estimates of fractional Po from the right panel.
	Fig 5. Estimation of Gβγ and Gα available for GIRK1/2 activation from macroscopic currents.(A, B) The method of estimation of number of Gβγ and Gα molecules per channel is exemplified for the high channel density group of Table 1. The same procedure has been applied to the low and intermediate density groups (Table 3). (A) Estimation of Gβγ available for channel activation utilizing Itotal. Simulated Itotal (green line) was calculated for a range of Gβγ surface densities using eqs 5–12, and compared with the experimentally observed Itotal. (B) Estimation of Gαi/o available for interaction with the channel. Simulated Ibasal (red line) was calculated using eqs 5–16 for a range of Gα surface densities, using the Gβγ density calculated in (A), and compared with the experimentally observed Ibasal. (C, D) The estimates of Gβγ:GIRK (C) and Gα:GIRK (D) ratios are stable in a wide range of GIRK-Gβγ interaction affinities, from KD = 5 nM to 100 nM. Simulations were done with the graded contribution model separately for the low-, intermediate- and high density groups from Table 1 (2.74, 9.7 and 21.7 channels/μm2, respectively).
	Fig 6. Dose-dependent activation of GIRK1/2 by coexpressed Gβγ: experiment and simulation.GIRK1/2 was expressed at 0.2 ng RNA. All data are mean ± SEM from one experiment. (A) Confocal images of Gβγ in giant excised plasma membranes stained with the anti-Gβ antibody. The intensity of all images was increased equally for a better viewing in this figure, but not in the process of image analysis. (B) Dose-dependence of Gβγ levels and Iβγ in oocytes injected with incrementing amounts of wt Gβγ RNA (0.05–30 ng per oocyte). Gβγ expression in the PM (grey bars) was measured from images shown in A, in 4–8 oocyte membranes, and Iβγ currents (red circles; right Y-axis) were measured in 12–16 oocytes. The dashed line shows the basal level of fluorescence, arising from the endogenous Gβγ. Note that, unlike in Western blots, in immunocytochemistry the antibody poorly recognized the endogenous Gβγ compared to the expressed bovine Gβγ. (C) Comparison of measured Iβγ and Rβγ (red circles) and simulated currents (curves). The relative Gβγ levels (from grey bars in B) have been converted into surface densities assuming that 5 ng Gβγ gives 30 molecules Gβγ/μm2. The blue line presents the simulation using graded contribution model and amounts of Gα and Gβγ (prior to coexpression of Gβγ) calculated using the methods described above: channel density was calculated from Iβγ (13.75 channels/μm2 with 5 ng Gβγ RNA in this experiment), and Gβγ and Gα were estimated from Itotal and Ibasal, giving 3.16 and 0.73 Gβγ:GIRK and Gα:GIRK ratios, respectively. For simulation with endogenous G proteins only and no Gβγ recruitment allowed (red, black and green lines), the channel density was the same and 1, 10 or 24 endogenous Gαβγ were assumed to be available for GIRK1/2.
	Fig 7. Estimated densities and calculated functional stoichiometries of the GIRK channel, Gβγ and Gαi/o in oocytes, HEK293 cells and neurons.Comparison of cultured mouse hippocampal neurons, and in oocytes and HEK293 cells expressing GIRK1/2. (A) Cells were subdivided into four groups according to the indicated Ibasal ranges, and channel densities were estimated assuming Iβγ = 2Itotal and Po,max = 0.105. Densities in Gα expression experiments in oocytes were estimated from Itotal in control groups of oocytes expressing GIRK1/2 and m2R only. (B, C) Estimates of Gβγ and Gα available for GIRK activation in the 4 channel density groups. In oocytes and HEK293 cells Ievoked was elicited by ACh via m2R, in neurons—by baclofen acting on GABAB receptors.
	Fig 8. Inverse relation between Ibasal and Ra arises from the decrease in Gα available for GIRK activation at higher Ibasal.(A) Gα molecules/channel as a function of channel density. Data for Gα:GIRK and channel density were adopted from Tables 1 and 3 (oocytes) and Table 4 (neurons). To generate a continuous curve, the channel density-Gα relationship was arbitrary fitted with a hyperbolic decay function of the form Gα = Yo + a/x, where x is channel density and a is a constant. (B) Simulated relation between Ibasal and channel density. We utilized eqs 5–15 and solved them numerically in the 1–30 channels/μm2 range, using constant values of Gβγ:GIRK ratio (3.5 for oocytes and 3.4 for neurons) and the calculated values of Gα:GIRK from the fitted curves shown in A. (C) Simulated relationship of Ibasal and Ra, with variable Gα:GIRK (from A) and constant Gβγ:GIRK ratios. Simulations with 4 Gβγ and 2 Gα (red line) or 4 Gβγ and 4 Gα (green line) available for one GIRK1/2 channel at all densities did not adequately describe the data.
	Fig 9. Schematic representation of the GPCR-G-protein-GIRK system.In resting state (no activated GPCR), the GIRK1/2 channel, a heterotetramer of 2 GIRK1 (grey) and 2 GIRK2 (green) subunits, is expected to interact with ~ 3–4 Gβγ subunits, two of which are bound to GαGDP subunits (GDP is shown by a yellow circle). For simplicity, the hypothetical Gβγ anchoring sites (which may be separate or partly overlapping with the Gβγ-activation sites) are not shown. The interaction of GIRK with Gβγ subunits is reversible. GαGDP can release the bound Gβγ in basal state, but since Gβγ-GαGDP interaction is of a high affinity, the probability of GIRK activation due to this process is relatively low. Thus, at any given time the channel is occupied by 2–3 Gβγ molecules (with an open probability of 6–26% of Po,max as shown in Fig 2C). GIRK overexpression leads to a decrease in GIRK:Gα ratio but does not change the GIRK:Gβγ ratio due to the additional recruitment of Gβγ by GIRK1/2, thus effectively increasing the proportion of channels occupied by > 3 Gβγ molecules, leading to an increase in “basal” open probability. The opposite process occurs upon overexpression of Gα, leading to a decrease in free Gβγ available for channel activation. On expression of Gβγ, its availability for channel activation increases, leading to higher fraction of 4 Gβγ-occupied channels with an open probability close to Po,max. Activation of G-proteins by an agonist (grey pentagon) via a GPCR (magenta) leads to an exchange of GDP to GTP (red circle) on Gα molecules, and to the subsequent dissociation of the Gαβγ heterotrimer, liberating additional Gβγ for channel activation.
	Fig 1. Basal and agonist-evoked GIRK currents in neurons and oocytes are inversely related.(A) A representative whole-recording of GIRK current in a neuron. Switching from low-K+ extracellular solution to a high-K+ solution led to the development of a large inward current probably carried by several ion channel types. Addition of baclofen elicited Ievoked. Arrows show the amplitudes of Ibasal, Ievoked and Itotal. Extent of activation, Ra, is defined as Itotal/Ibasal. (B) Inverse correlation between Ibasal and Ra in oocytes and neurons. To allow direct comparison of Ibasal in oocytes and neurons, currents in neurons were corrected for the 10 mV difference in holding potential, which was -70 mV in neurons and -80 mV in oocytes (see Methods). The correlation between Ra and Ibasal was highly significant, p = 0.000000028 (neurons; n = 60; correlation coefficient = -0.633) and p = 0.0000002 (oocytes; n = 272; correlation coefficient = -0.728) by Spearman correlation test.

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