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.

Bamford, Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors. 2018, Pubmed

Bamford, Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors. 2018, Pubmed
Ben Chaim, Voltage affects the dissociation rate constant of the m2 muscarinic receptor. 2013, Pubmed , Xenbase
Ben-Chaim, The M2 muscarinic G-protein-coupled receptor is voltage-sensitive. 2003, Pubmed , Xenbase
Ben-Chaim, Movement of 'gating charge' is coupled to ligand binding in a G-protein-coupled receptor. 2006, Pubmed , Xenbase
Benians, Agonist unbinding from receptor dictates the nature of deactivation kinetics of G protein-gated K+ channels. 2003, Pubmed
Birk, Membrane Potential Controls the Efficacy of Catecholamine-induced β1-Adrenoceptor Activity. 2015, Pubmed
Bruns, Preclinical profile of a dopamine D1 potentiator suggests therapeutic utility in neurological and psychiatric disorders. 2018, Pubmed
Bünemann, Activation and deactivation kinetics of alpha 2A- and alpha 2C-adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents. 2001, Pubmed
Carr, The Dopamine D5 Receptor Is Involved in Working Memory. 2017, Pubmed
Goldman-Rakic, Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction. 2004, Pubmed
Hansen, Xenopus oocyte electrophysiology in GPCR drug discovery. 2009, Pubmed , Xenbase
Hatcher-Solis, G protein-coupled receptor signaling to Kir channels in Xenopus oocytes. 2014, Pubmed , Xenbase
Huang, D1 dopamine receptors. 2001, Pubmed
Kalinowski, A receptor linked to a Gi-family G-protein functions in initiating oocyte maturation in starfish but not frogs. 2003, Pubmed , Xenbase
Kurz, Voltage Dependence of Prostanoid Receptors. 2020, Pubmed
Lewis, Discovery of D1 Dopamine Receptor Positive Allosteric Modulators: Characterization of Pharmacology and Identification of Residues that Regulate Species Selectivity. 2015, Pubmed
Lim, A G protein-gated K channel is activated via beta 2-adrenergic receptors and G beta gamma subunits in Xenopus oocytes. 1995, Pubmed , Xenbase
Luderman, Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites. 2018, Pubmed
López-Serrano, Voltage-induced structural modifications on M2 muscarinic receptor and their functional implications when interacting with the superagonist iperoxo. 2020, Pubmed
Marcellino, Increased affinity of dopamine for D(2) -like versus D(1) -like receptors. Relevance for volume transmission in interpreting PET findings. 2012, Pubmed
Marcott, Phasic dopamine release drives rapid activation of striatal D2-receptors. 2014, Pubmed
Moreno-Galindo, Relaxation gating of the acetylcholine-activated inward rectifier K+ current is mediated by intrinsic voltage sensitivity of the muscarinic receptor. 2011, Pubmed
Ohana, The metabotropic glutamate G-protein-coupled receptors mGluR3 and mGluR1a are voltage-sensitive. 2006, Pubmed , Xenbase
Sahlholm, Agonist-specific voltage sensitivity at the dopamine D2S receptor--molecular determinants and relevance to therapeutic ligands. 2011, Pubmed , Xenbase
Sahlholm, Voltage sensitivities and deactivation kinetics of histamine H₃ and H₄ receptors. 2012, Pubmed , Xenbase
Sahlholm, Voltage-dependence of the human dopamine D2 receptor. 2008, Pubmed , Xenbase
Sahlholm, The role of RGS protein in agonist-dependent relaxation of GIRK currents in Xenopus oocytes. 2011, Pubmed , Xenbase
Sahlholm, Differential voltage-sensitivity of D2-like dopamine receptors. 2008, Pubmed , Xenbase
Sariñana, Differential roles of the dopamine 1-class receptors, D1R and D5R, in hippocampal dependent memory. 2014, Pubmed
Sawaguchi, The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. 1994, Pubmed
Sidhu, Multiple coupling of human D5 dopamine receptors to guanine nucleotide binding proteins Gs and Gz. 1998, Pubmed
So, Calcium signaling by dopamine D5 receptor and D5-D2 receptor hetero-oligomers occurs by a mechanism distinct from that for dopamine D1-D2 receptor hetero-oligomers. 2009, Pubmed
Touhara, Molecular basis of signaling specificity between GIRK channels and GPCRs. 2018, Pubmed
Vivaudou, Probing the G-protein regulation of GIRK1 and GIRK4, the two subunits of the KACh channel, using functional homomeric mutants. 1997, Pubmed , Xenbase
Vorobiov, Coupling of the muscarinic m2 receptor to G protein-activated K(+) channels via Galpha(z) and a receptor-Galpha(z) fusion protein. Fusion between the receptor and Galpha(z) eliminates catalytic (collision) coupling. 2000, Pubmed , Xenbase
Weinshank, Molecular cloning and characterization of a high affinity dopamine receptor (D1 beta) and its pseudogene. 1991, Pubmed
Wellner-Kienitz, Overexpression of beta 1 and beta 2 adrenergic receptors in rat atrial myocytes. Differential coupling to G protein-gated inward rectifier K(+) channels via G(s) and G(i)/o. 2001, Pubmed
Yang, D1 dopamine receptors intrinsic activity and functional selectivity affect working memory in prefrontal cortex. 2021, Pubmed
de la Peña, Gs couples thyrotropin-releasing hormone receptors expressed in Xenopus oocytes to phospholipase C. 1995, Pubmed , Xenbase
Ågren, The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation. 2018, Pubmed , Xenbase
Ågren, Point mutation of a conserved aspartate, D69, in the muscarinic M2 receptor does not modify voltage-sensitive agonist potency. 2018, Pubmed , Xenbase