Ågren R , Sahlholm K .

             inward rectifier potassium channel activity

                Parkinson's disease
                schizophrenia

Figure 1. Voltage-sensitive potency and G protein-dependence of GIRK activation by D1-like receptors. (A) Representative traces of D1R-evoked GIRK currents upon application and washout of 100 nM, 1, and 30 µM DA at 0 (blue) and -80 mV (black). (B) Representative traces of D5R-evoked GIRK currents upon application and washout of 10 nM, 100 nM, and 3 µM DA at 0 (red) and -80 mV (black). (C) Concentration-response curves for D1R-evoked GIRK current at -80 mV and 0 mV. The pEC50 for DA was 6.902 ± 0.120 (125 nM; Hill slope 1.419 ± 0.348) and 6.043 ± 0.078 (906 nM; Hill slope 1.074 ± 0.165) at -80 mV and 0 mV, respectively (n = 3 - 5). *p < 0.05, **p < 0.01, ***p < 0.001, Student’s paired t-test. (D) Concentration-response curves for D5R-evoked GIRK current at -80 mV and 0 mV. The pEC50 for DA was 8.211 ± 0.065 (6 nM; Hill slope 1.301 ± 0.166) and 7.361 ± 0.078 (44 nM; Hill slope 0.959 ± 0.116) at -80 mV and 0 mV, respectively (n = 6). ***p < 0.001, Student’s paired t-test, §p < 0.05, Wilcoxon signed rank test. Curves were obtained by fitting a variable-slope sigmoidal function to the data using least squares nonlinear regression (see Methods). (E) Mean currents (± SEM) evoked by 10 µM DA in oocytes expressing D1R and GIRK1/4 with or without PTX-S1 or Gαs antisense oligonucleotide at 0 mV (top) and -80 mV (bottom). At -80 mV, mean currents were -1.12 ± 0.21 µA (D1R; n = 7), -1.06 ± 0.15 µA (+PTX-S1; n = 7), and -0.43 ± 0.13 µA (+Gαs antisense oligonucleotide; n = 6). At 0 mV, mean currents were 0.025 ± 0.007 µA (D1R; n = 7), 0.020 ± 0.003 µA (+PTX-S1; n = 7), and 0.006 ± 0.004 µA (+Gαs antisense oligonucleotide; n = 7). *; p<0.05, Tukey’s multiple comparisons test. (F) Mean currents (± SEM) evoked by 10 µM DA in oocytes expressing D5R and GIRK1/4 with or without PTX-S1, and Gαs antisense oligonucleotide at 0 mV (top) and -80 mV (bottom). At -80 mV, mean currents were -2.92 ± 0.35 µA (D5R; n = 7), -1.05 ± 0.16 µA (+PTX-S1; n = 6), and 0.012 ± 0.021 µA (+PTX-S1+Gαs antisense oligonucleotide; n = 3). Note that in the presence of antisense oligonucleotide, there was a small deflection in positive direction during DA application. At 0 mV, mean currents were 0.100 ± 0.018 µA (D5R; n = 7), 0.029 ± 0.005 µA (+PTX-S1; n = 6) and 0.006 ± 0.010 µA (+PTX-S1+Gαs antisense oligonucleotide; n = 4). ***p < 0.001, Tukey’s multiple comparisons test. §p < 0.05, §§p < 0.01, Kruskal-Wallis test with Dunn’s multiple comparisons test.

Figure 2. Current deactivation rate upon DA washout. Following depolarization, the deactivation rate increased at the D1R (-80 mV; 0.070 ± 0.005 s-1, 0 mV; 0.097 ± 0.011 s-1; n = 12 for both potentials; p = 0.0049, Wilcoxon signed rank test) and D5R (-80 mV; 0.034 ± 0.004 s-1, 0 mV; 0.072 ± 0.009 s-1; n = 15 for both potentials; p < 0.001, Wilcoxon signed rank test) following depolarization. Horizontal bars indicate means ± SEM. **, p = 0.0049; ***, p < 0.001.

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