Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease
Abstract
:1. Kir2.x Expression, Structure and Rectification
2. Kir2.x Disease Relationships
3. AgoKirs, Agonists of Kir2.x Function
3.1. Indirect Activators
3.1.1. Aldosterone
3.1.2. Isoproterenol
3.1.3. Tenidap
3.1.4. Valsartan
3.1.5. Zacopride
3.2. Direct Activators
3.2.1. Flecainide
3.2.2. Propafenone
3.2.3. Timolol
3.2.4. Pregnenolone Sulfate
3.3. Unknown Mechanism of Activation
3.3.1. LPS (lipopolysaccharides)
3.3.2. Morphine
3.3.3. Polydatin
4. Lead Compounds and Clinical Perspective
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AF | Atrial Fibrillation |
AgoKir | Agonist of Kir channel |
AS | Andersen Syndrome |
CFTR | Cystic Fibrosis Transmembrane Conductance Regulator |
CHO | Chinese Hamster Ovary |
EK | Potassium equilibrium potential |
HEK | Human Embryonal Kidney |
HF | Heart Failure |
IK1 | Inward rectifier current |
IKATP | ATP regulated inward rectifier current |
ISO | Isoproterenol/isoprenaline |
Kir2.x | Isoform x of the inward rectifier protein Kir2 family |
LPS | Lipopolysacharides |
MI | Myocardial Infarction |
MR | Mineral corticoid Receptor |
PD | Polydatin |
PKA | Protein Kinase A |
PKC | Protein Kinase C |
PREGS | Pregnenolone Sulfate |
RAAS | Renin-Angiotensin-Aldosterone-System |
Vm | Membrane potential |
ZAC | Zacopride |
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Compound | Readout | Test System | Dose-Effect Relation | Mechanism of Action | Ref. |
---|---|---|---|---|---|
Direct activators | |||||
Flecainide | C | CHO cells | IKir2.1 EC50/Emax (−50 mV) = 0.4 ± 0.01 μM/53.9 ± 3.6% IKir2.1 EC50/Emax (−120 mV) = 0.8 ± 0.01 μM/22.0 ± 1.96% | Interaction with Cys311 | [31] |
C | guinea pig ventricular cmc | IK1 1 μM: 19.5 ± 3.2% (−120 mV); 38.0 ± 9.5% (−40 mV) | Interaction with Cys311 | [31] | |
PREGS | C | Xenopus oocytes | IKir2.3 EC50 (−70 mV) = 15.6 ± 0.9 μM | Binding extracellular site | [32] |
Propafenone | C | CHO cells | IKir2.1 EC50/Emax (−50 mV) = 12.0 ± 3.0 nM/42.0 ± 2.6% | Interaction with Cys311 | [33] |
C | guinea pig ventricular cmc | IK1 0.5 μM: approx 45 ± 5% (−40 mV) | Interaction with Cys311 | [33] | |
Timolol | C | CHO cells | IKir2.1 EC50 (−50 mV) = 3.2 ± 0.3 nM | Interaction with Cys311 | [33] |
Indirect activators | |||||
Aldosterone | C | rabbit ventricular cmc | IK1 10 nM: 1.6-fold increase NPo of 30 pS current | MR-independent activation | [34] |
rat ventricle | Kir2.1 2.24 mg/h/kg 4 wks: approx. 1.57 ± 0.14 fold Kir2.3 2.24 mg/h/kg 4 wks: approx. 1.26 ± 0.15 fold (ns) | Unknown Unknown | [35] | ||
Isoproterenol | C | Xenopus oocytes | IKir2.1 EC50 = 27.4 nM * IKir2.2 EC50 = 17.8 nM * | PKC dependent via β3-AR PKA dependent via β3-AR | [36] |
Valsartan | R,P | rat ventricle | 10 mg/kg/day for 7 days prevented Kir2.1 downregulation | Casein Kinase 2 inhibition and/or Th1 immune response inhibition and/or NF-κB-miR-16 pathway | [37,38,39] |
R,P | ventricular cmc, H9c2 cells | 20 μM (48 h) prevented Kir2.1 downregulation | Casein Kinase 2 inhibition and/or Th1 immune response inhibition and/or NF-κB-miR-16 pathway | [37,38,39] | |
C | rat ventricular cmc | 20 μM (48 h) prevented IK1 inward current downregulation | Th1 immune response inhibition | [38] | |
Zacopride | C | rat atrial cmc, HEK-293 cells | IKir2.1 EC50 (−50 mV) = 30.7 nM IKir2.1 (−50 mV) = 40.7 ± 9.7% | PKA dependent | [40] |
LPS | P,C | mouse pulmonary micro-vascular endothelial cells | 10 ng/mL (up to 24 h): 1.5-fold increase Kir2.1 10 ng/mL IKir2.1 (inward/outward) = approx. 1.7-fold | Unknown | [41] |
Morphine | C | rabbit ventricular cmc | IK1 (−60 mV) = 25 ± 9% (0.1 μM); 32 ± 11% (1 μM) | Opioid-receptor pathway independent | [42] |
Polydatin | C | rat ventricular cmc | IK1 10 μM: approx. 40% (−100 mV) | Unknown | [43] |
Tenidap | C | CHO cells | IKir2.3 EC50 = 1.3 μM * | Extracellularly, unaffected by pA2, PKC, and AA secondary pathways | [44] |
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van der Schoor, L.; van Hattum, E.J.; de Wilde, S.M.; Harlianto, N.I.; van Weert, A.-J.; Bloothooft, M.; van der Heyden, M.A.G. Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease. Int. J. Mol. Sci. 2020, 21, 5746. https://doi.org/10.3390/ijms21165746
van der Schoor L, van Hattum EJ, de Wilde SM, Harlianto NI, van Weert A-J, Bloothooft M, van der Heyden MAG. Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease. International Journal of Molecular Sciences. 2020; 21(16):5746. https://doi.org/10.3390/ijms21165746
Chicago/Turabian Stylevan der Schoor, Laura, Emma J. van Hattum, Sophie M. de Wilde, Netanja I. Harlianto, Aart-Jan van Weert, Meye Bloothooft, and Marcel A. G. van der Heyden. 2020. "Towards the Development of AgoKirs: New Pharmacological Activators to Study Kir2.x Channel and Target Cardiac Disease" International Journal of Molecular Sciences 21, no. 16: 5746. https://doi.org/10.3390/ijms21165746