Liu C , Chen IS , Tateyama M , Kubo Y .

             G-protein gated potassium channel activity

	Figure 1. The effects of BD1047 and BD1063 on GIRK channels. A, left: the pulse protocol for recording; Middle: chemical structure of BD1047; Right: chemical structure of BD1063. B–E, left: representative current traces measured in Xenopus oocytes; Right: The time-lapse changes of the current amplitudes at −100 mV (orange plots) and at +40 mV (gray dots) in ND96, 96K+ and 96K+ with 100 μM BD1047 solution in oocytes expressing (B) GIRK1/2, (C) GIRK2, (D) GIRK1/4 or (E) GIRK4+Gβγ channels. BD1047 was applied and washed out by constant bath perfusion using a peristaltic pump. F, inhibition by 100 μM BD1047, of GIRK1/2, GIRK2, GIRK1/4, and GIRK4+Gβγ channel currents. G, inhibition by 100 μM BD1047, of GIRK1/2, GIRK2, GIRK1/4 and GIRK4 channel currents when Gβγ subunits were co-expresssed. F and G, data are mean ± SD (n = 5 for each); One way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05; ∗∗ indicates p < 0.01. H, inhibition by 100 μM BD1063, of GIRK2+Gβγ and GIRK4+Gβγ channel currents. Data are mean ± SD (n = 5 for each); Student’s t test (unpaired), ∗∗ indicates p < 0.01.
	Figure 2. Dose inhibition relationships of BD1047 on GIRK2 and GIRK4 current. A, the pulse protocol for recording and the recorded current traces in 96K+, with 10 μM BD1047 or 100 μM BD1047. B, IV-relationship of GIRK4 in an extracellular solution containing 96K+, with 10 μM BD1047 or 100 μM BD1047. C, the normalized current at −120 mV, −100 mV, −80 mV and −60 mV in different extracellular solution (Black: 96K+, blue: 10 μM BD1047 or magenta: 100 μM BD1047). The current amplitude of 10 μM BD1047 or 100 μM BD1047 relative to 96K+ (I10 μM BD/I96K+ or I100 μM BD/I96K+) at each potential were calculated. Data are mean ± SD (n = 3) for each plot. D, the pulse protocol for recording in (E) and (F). E and F, left: representative current recordings in Xenopus oocytes evoked by the voltage protocol shown above. BD1047 ranging in concentration from 0.1 μM to 500 μM was applied to GIRK2 (E) and GIRK4 (F) channels. Right: the time courses of the current changes in various concentrations of BD1047 in oocytes expressing (E) GIRK2 or (F) GIRK4 channels. Orange dots indicate the recorded current amplitudes at −100 mV and gray dots indicate those at +40 mV. G, dose–inhibition relationships of BD1047 on GIRK2 (blue) and GIRK4 channel (black). Data are mean ± SD (n = 4–5) for each plot. IC50 is 75.4 ± 9.7 μM (GIRK2) and 17.4 ± 3.7 μM (GIRK4), respectively.
	Figure 3. Effects of BD1047 on ACh-induced GIRK channel in rat atrial myocytes. A, the voltage recording protocol used for patch-clamp recording from atrial myocytes. B and E, the timelapse change of whole-cell currents recorded from the rat atrial myocytes in 20 mM K+ solution with (B) 1 μM ACh alone, (C) ACh with 3 μM TPN-Q (green bar), (D) ACh with 10 μM BD1047 (red bar) or (E) 100 μM of BD1047 (red bar). F, comparison of the normalized current after the application of inhibitor for 27 s. The control group indicates the desensitization of ACh-induced current which is calculated at the same time point as other groups. Data are mean ± SD (n = 5–7 for each); One way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01. G, dose–inhibition relationships of BD1047 on ACh-induced GIRK channel. Data are mean ± SD (n = 2–5) for each plot. IC50 is 7.5 ± 1.0 μM.
	Figure 4. The effects of BD1047 on GIRK2/4 chimeras. A, chimeric constructs were generated in which 5 regions of GIRK2 (N-ter, TM1, the pore-forming loop between TM1 and TM2, TM2 and C-ter) were substituted with the corresponding regions of GIRK4. B, schematic drawing of six chimeras, GIRK42222, GIRK24222, GIRK22422, GIRK22242, GIRK22224, and GIRK24242. Red letters “4” indicate those swapped to the corresponding part from GIRK4. C, comparison of the inhibition percentages before and after the application of 100 μM BD1047 to GIRK42222, GIRK24222, GIRK22422, GIRK22242, GIRK22224 and GIRK24242 chimeras. Gβγ subunits are co-expressed in all cases. D, schematic drawings of GIRK2/4 N-ter chimeras. GIRK2 4(1–86)2222 includes the whole 86 amino acids of N-ter from GIRK4, and GIRK2 4(1–58)2222 includes the distal 58 amino acids of N-ter from GIRK4. E, comparison of the inhibition percentages before and after the application of 100 μM BD1047. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05, ∗∗ indicates p < 0.01.
	Figure 5. The effects of BD 1047 on GIRK2 and GIRK4 mutants. A, the amino acid sequence alignment of mouse GIRK2 and rat GIRK4. A red dotted line indicates the start of the proximal N-ter of GIRK2 and GIRK4. Red arrows indicate non-conserved amino acids in the proximal N-ter region. Green arrows indicate the possible binding sites of BD1047 to GIRK4 on the pore-forming region. Blue arrows indicate the possible binding sites between BD1047 and GIRK4 on the C-ter. B, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK2, GIRK4, GIRK2 4(1–86)2222, GIRK2 R73Q, GIRK2 T80S and GIRK2 I82L. C, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK2, GIRK2 I82L, GIRK4 and GIRK L77I. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05; ∗∗ indicates p < 0.01.
	Figure 6. Computational molecular docking of BD1047 to GIRK4 and GIRK2. A and B, the homology structure model of GIRK4 (A) and GIRK4 L77I (B) based on the structure of GIRK2 (6XIT). Cyan clusters of BD1047 indicate the predicted dockings of BD1047 to GIRK4 WT or GIRK4 L77I in various directions and orientations. Leu77 or Ile77 is highlighted in pink color. C and D, the structure of GIRK2 (6XIT) (C) and homology structure model of GIRK2 I82L (D) based on the GIRK2. Cyan clusters of BD1047 indicate the predicted dockings of BD1047 to GIRK2 WT or GIRK2 I82L in various directions and orientations. Ile82 or Leu82 is highlighted in pink color. The right panels are an enlarged image of BD1047 docking on N-ter region in each left panel.
	Figure 7. Computational molecular docking of GIRK4 and BD 1047 showing the contribution of amino acid residues adjacent to Leu77. A, the predicted protein structure is the homology model of GIRK4 based upon the structure of GIRK2 (6XIT). Cyan clusters of BD1047 indicate the predicted dockings in various directions and orientations of BD1047. Tyr73, Leu74, Leu77, Thr80, Leu81, and Lue84 are highlighted in red, magenta, pink, purple, orange and yellow colors, respectively. Right panels are enlarged images of Leu77 and adjacent amino acid residues for BD interaction from the left panel. B, the effects of BD1047 on GIRK4 and its mutants of the predicted docking sites. Comparison of the inhibition percentages before and after the application of 100 μM BD1047 on oocytes expressing GIRK4, GIRK4 L77I, GIRK4 L74A, GIRK4 L81A, and GIRK4 L84A. Data are mean ± SD (n = 4 for each); one-way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01.
	Figure 8. Identification of the binding sites of BD1047 to GIRK4 in the pore-forming region and the C-ter. A and B, using the homology model of GIRK4 based on the structure of GIRK2 (6XIT), cyan clusters of BD1047 indicate the predicted dockings in various directions and orientations of BD1047. A, the possible binding sites of BD1047 on the pore-forming region of GIRK4. Glu174 and Thr149 are highlighted in pink. B, the possible binding sites of BD1047 on the C-ter region of GIRK4. Glu298 and Glu300 are highlighted in pink. C, representative current recordings in ND96, 96K+, 96K+ with 100 μM BD1047 of GIRK4 WT, GIRK4 E147A, GIRK4 T149A, GIRK4 E289A, and GIRK4 E300A in Xenopus oocytes evoked by the voltage protocol shown in the figure. Gβγ subunits are co-expressed in all five cases. D, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK4 WT, GIRK4 E147A, and GIRK4 E289A. E, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK4 WT, GIRK4 E147A, and GIRK4 E147Q. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01.
	Figure 9. Competition between BD1047 and IVM at GIRK4. A, the amino acid sequence alignment of mouse GIRK2 and rat GIRK4. The blue arrow and red arrow indicate the Ile82 of GIRK2 and the corresponding amino acid Leu77 on GIRK4, respectively. B, the effects of 100 μM IVM on the concentration-response relationship of BD1047 on the GIRK4 channel. Left and middle: the representative current recordings in Xenopus oocytes. Various concentrations of BD1047 from 0.1 μM to 500 μM were applied to the GIRK4 channel in the absence of IVM (left) and presence of IVM (middle). Right: Dose-inhibition relationships of BD1047 on GIRK4 channel in the absence of IVM (black) and presence of IVM (blue). Data are mean ± SD (n = 4–5) for each plot. IC50 is 19.6 ± 0.5 (μM) (-IVM) and 62.9 ± 0.5 (μM) (+IVM), respectively. C, the timelapse changes of the current amplitudes at −100 mV (orange plots) in 96K+, ND96 and 96K+ with 100 μM BD1047 solution in oocytes only expressing GIRK4+Gβγ channels. D, the timelapse changes of the current amplitudes at −100 mV (orange plots) in 96K+, ND96 (black bar), 96K+ with 100 μM IVM (green bar), 96K+ with 100 μM BD1047 (red bar) and IVM solution (green bar). E, effects of IVM on the inhibition kinetics of BD1047 on GIRK4 current. The inhibition kinetics were calculated from the current amplitude at −100 mV after the application of BD1047 in the absence or presence of IVM. The maximal reduction of current after the application of BD1047 was normalized as 1. F, Tau of BD’ inhibition calculated from (E). Data are mean ± SD (n = 4 for each); unpaired t test, ∗∗∗ indicates p < 0.001.
	Figure 10. Comparison of the side chain between GIRK4 and GIRK2. A, the chemical structure of leucine. The Isobutyl side chain is highlighted with a red frame. B, the chemical structure of isoleucine. Secbutyl side chain is highlighted with a red frame. C, left: the overlay of the structure of GIRK2 WT (6XIT) (yellow color) and homology model of GIRK4 L77I based on GIRK2 (6XIT) (cyan color). Right: an enlarged image from the left panel. D, left: the overlay of the structure of the homology model of GIRK4 WT based on GIRK2 (6XIT) (gray color) and the homology model of GIRK2 I82L based on GIRK2 (6XIT) (orange color). Right: an enlarged image from the left panel.
	Figure 1. The effects of BD1047 and BD1063 on GIRK channels.A, left: the pulse protocol for recording; Middle: chemical structure of BD1047; Right: chemical structure of BD1063. B–E, left: representative current traces measured in Xenopus oocytes; Right: The time-lapse changes of the current amplitudes at −100 mV (orange plots) and at +40 mV (gray dots) in ND96, 96K+ and 96K+ with 100 μM BD1047 solution in oocytes expressing (B) GIRK1/2, (C) GIRK2, (D) GIRK1/4 or (E) GIRK4+Gβγ channels. BD1047 was applied and washed out by constant bath perfusion using a peristaltic pump. F, inhibition by 100 μM BD1047, of GIRK1/2, GIRK2, GIRK1/4, and GIRK4+Gβγ channel currents. G, inhibition by 100 μM BD1047, of GIRK1/2, GIRK2, GIRK1/4 and GIRK4 channel currents when Gβγ subunits were co-expresssed. F and G, data are mean ± SD (n = 5 for each); One way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05; ∗∗ indicates p < 0.01. H, inhibition by 100 μM BD1063, of GIRK2+Gβγ and GIRK4+Gβγ channel currents. Data are mean ± SD (n = 5 for each); Student’s t test (unpaired), ∗∗ indicates p < 0.01.
	Figure 2. Dose inhibition relationships of BD1047 on GIRK2 and GIRK4 current.A, the pulse protocol for recording and the recorded current traces in 96K+, with 10 μM BD1047 or 100 μM BD1047. B, IV-relationship of GIRK4 in an extracellular solution containing 96K+, with 10 μM BD1047 or 100 μM BD1047. C, the normalized current at −120 mV, −100 mV, −80 mV and −60 mV in different extracellular solution (Black: 96K+, blue: 10 μM BD1047 or magenta: 100 μM BD1047). The current amplitude of 10 μM BD1047 or 100 μM BD1047 relative to 96K+ (I10 μM BD/I96K+ or I100 μM BD/I96K+) at each potential were calculated. Data are mean ± SD (n = 3) for each plot. D, the pulse protocol for recording in (E) and (F). E and F, left: representative current recordings in Xenopus oocytes evoked by the voltage protocol shown above. BD1047 ranging in concentration from 0.1 μM to 500 μM was applied to GIRK2 (E) and GIRK4 (F) channels. Right: the time courses of the current changes in various concentrations of BD1047 in oocytes expressing (E) GIRK2 or (F) GIRK4 channels. Orange dots indicate the recorded current amplitudes at −100 mV and gray dots indicate those at +40 mV. G, dose–inhibition relationships of BD1047 on GIRK2 (blue) and GIRK4 channel (black). Data are mean ± SD (n = 4–5) for each plot. IC50 is 75.4 ± 9.7 μM (GIRK2) and 17.4 ± 3.7 μM (GIRK4), respectively.
	Figure 3. Effects of BD1047 on ACh-induced GIRK channel in rat atrial myocytes.A, the voltage recording protocol used for patch-clamp recording from atrial myocytes. B and E, the timelapse change of whole-cell currents recorded from the rat atrial myocytes in 20 mM K+ solution with (B) 1 μM ACh alone, (C) ACh with 3 μM TPN-Q (green bar), (D) ACh with 10 μM BD1047 (red bar) or (E) 100 μM of BD1047 (red bar). F, comparison of the normalized current after the application of inhibitor for 27 s. The control group indicates the desensitization of ACh-induced current which is calculated at the same time point as other groups. Data are mean ± SD (n = 5–7 for each); One way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01. G, dose–inhibition relationships of BD1047 on ACh-induced GIRK channel. Data are mean ± SD (n = 2–5) for each plot. IC50 is 7.5 ± 1.0 μM.
	Figure 4. The effects of BD1047 on GIRK2/4 chimeras.A, chimeric constructs were generated in which 5 regions of GIRK2 (N-ter, TM1, the pore-forming loop between TM1 and TM2, TM2 and C-ter) were substituted with the corresponding regions of GIRK4. B, schematic drawing of six chimeras, GIRK42222, GIRK24222, GIRK22422, GIRK22242, GIRK22224, and GIRK24242. Red letters “4” indicate those swapped to the corresponding part from GIRK4. C, comparison of the inhibition percentages before and after the application of 100 μM BD1047 to GIRK42222, GIRK24222, GIRK22422, GIRK22242, GIRK22224 and GIRK24242 chimeras. Gβγ subunits are co-expressed in all cases. D, schematic drawings of GIRK2/4 N-ter chimeras. GIRK2 4(1–86)2222 includes the whole 86 amino acids of N-ter from GIRK4, and GIRK2 4(1–58)2222 includes the distal 58 amino acids of N-ter from GIRK4. E, comparison of the inhibition percentages before and after the application of 100 μM BD1047. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05, ∗∗ indicates p < 0.01.
	Figure 5. The effects of BD 1047 on GIRK2 and GIRK4 mutants.A, the amino acid sequence alignment of mouse GIRK2 and rat GIRK4. A red dotted line indicates the start of the proximal N-ter of GIRK2 and GIRK4. Red arrows indicate non-conserved amino acids in the proximal N-ter region. Green arrows indicate the possible binding sites of BD1047 to GIRK4 on the pore-forming region. Blue arrows indicate the possible binding sites between BD1047 and GIRK4 on the C-ter. B, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK2, GIRK4, GIRK2 4(1–86)2222, GIRK2 R73Q, GIRK2 T80S and GIRK2 I82L. C, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK2, GIRK2 I82L, GIRK4 and GIRK L77I. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗ indicates p < 0.05; ∗∗ indicates p < 0.01.
	Figure 6. Computational molecular docking of BD1047 to GIRK4 and GIRK2.A and B, the homology structure model of GIRK4 (A) and GIRK4 L77I (B) based on the structure of GIRK2 (6XIT). Cyan clusters of BD1047 indicate the predicted dockings of BD1047 to GIRK4 WT or GIRK4 L77I in various directions and orientations. Leu77 or Ile77 is highlighted in pink color. C and D, the structure of GIRK2 (6XIT) (C) and homology structure model of GIRK2 I82L (D) based on the GIRK2. Cyan clusters of BD1047 indicate the predicted dockings of BD1047 to GIRK2 WT or GIRK2 I82L in various directions and orientations. Ile82 or Leu82 is highlighted in pink color. The right panels are an enlarged image of BD1047 docking on N-ter region in each left panel.
	Figure 7. Computational molecular docking of GIRK4 and BD 1047 showing the contribution of amino acid residues adjacent to Leu77.A, the predicted protein structure is the homology model of GIRK4 based upon the structure of GIRK2 (6XIT). Cyan clusters of BD1047 indicate the predicted dockings in various directions and orientations of BD1047. Tyr73, Leu74, Leu77, Thr80, Leu81, and Lue84 are highlighted in red, magenta, pink, purple, orange and yellow colors, respectively. Right panels are enlarged images of Leu77 and adjacent amino acid residues for BD interaction from the left panel. B, the effects of BD1047 on GIRK4 and its mutants of the predicted docking sites. Comparison of the inhibition percentages before and after the application of 100 μM BD1047 on oocytes expressing GIRK4, GIRK4 L77I, GIRK4 L74A, GIRK4 L81A, and GIRK4 L84A. Data are mean ± SD (n = 4 for each); one-way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01.
	Figure 8. Identification of the binding sites of BD1047 to GIRK4 in the pore-forming region and the C-ter.A and B, using the homology model of GIRK4 based on the structure of GIRK2 (6XIT), cyan clusters of BD1047 indicate the predicted dockings in various directions and orientations of BD1047. A, the possible binding sites of BD1047 on the pore-forming region of GIRK4. Glu174 and Thr149 are highlighted in pink. B, the possible binding sites of BD1047 on the C-ter region of GIRK4. Glu298 and Glu300 are highlighted in pink. C, representative current recordings in ND96, 96K+, 96K+ with 100 μM BD1047 of GIRK4 WT, GIRK4 E147A, GIRK4 T149A, GIRK4 E289A, and GIRK4 E300A in Xenopus oocytes evoked by the voltage protocol shown in the figure. Gβγ subunits are co-expressed in all five cases. D, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK4 WT, GIRK4 E147A, and GIRK4 E289A. E, comparison of the inhibition percentages before and after the application of 100 μM BD1047 on GIRK4 WT, GIRK4 E147A, and GIRK4 E147Q. Data are mean ± SD (n = 4–5 for each); one-way ANOVA followed by Tukey’s test, ∗∗ indicates p < 0.01.
	Figure 9. Competition between BD1047 and IVM at GIRK4.A, the amino acid sequence alignment of mouse GIRK2 and rat GIRK4. The blue arrow and red arrow indicate the Ile82 of GIRK2 and the corresponding amino acid Leu77 on GIRK4, respectively. B, the effects of 100 μM IVM on the concentration-response relationship of BD1047 on the GIRK4 channel. Left and middle: the representative current recordings in Xenopus oocytes. Various concentrations of BD1047 from 0.1 μM to 500 μM were applied to the GIRK4 channel in the absence of IVM (left) and presence of IVM (middle). Right: Dose-inhibition relationships of BD1047 on GIRK4 channel in the absence of IVM (black) and presence of IVM (blue). Data are mean ± SD (n = 4–5) for each plot. IC50 is 19.6 ± 0.5 (μM) (-IVM) and 62.9 ± 0.5 (μM) (+IVM), respectively. C, the timelapse changes of the current amplitudes at −100 mV (orange plots) in 96K+, ND96 and 96K+ with 100 μM BD1047 solution in oocytes only expressing GIRK4+Gβγ channels. D, the timelapse changes of the current amplitudes at −100 mV (orange plots) in 96K+, ND96 (black bar), 96K+ with 100 μM IVM (green bar), 96K+ with 100 μM BD1047 (red bar) and IVM solution (green bar). E, effects of IVM on the inhibition kinetics of BD1047 on GIRK4 current. The inhibition kinetics were calculated from the current amplitude at −100 mV after the application of BD1047 in the absence or presence of IVM. The maximal reduction of current after the application of BD1047 was normalized as 1. F, Tau of BD’ inhibition calculated from (E). Data are mean ± SD (n = 4 for each); unpaired t test, ∗∗∗ indicates p < 0.001.
	Figure 10. Comparison of the side chain between GIRK4 and GIRK2.A, the chemical structure of leucine. The Isobutyl side chain is highlighted with a red frame. B, the chemical structure of isoleucine. Secbutyl side chain is highlighted with a red frame. C, left: the overlay of the structure of GIRK2 WT (6XIT) (yellow color) and homology model of GIRK4 L77I based on GIRK2 (6XIT) (cyan color). Right: an enlarged image from the left panel. D, left: the overlay of the structure of the homology model of GIRK4 WT based on GIRK2 (6XIT) (gray color) and the homology model of GIRK2 I82L based on GIRK2 (6XIT) (orange color). Right: an enlarged image from the left panel.

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