ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005


The Latest on Twitter

Kidney Week

Abstract: TH-PO325

Discovery and Characterization of VU0493206, the First Small-Molecule Activator of Kir4.1/Kir5.1 Channels

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic


  • Mcclenahan, Samantha J., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Isaeva, Elena, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  • Klemens, Christine Anne, University of South Florida, Tampa, Florida, United States
  • Staruschenko, Alexander, University of South Florida, Tampa, Florida, United States
  • Denton, Jerod S., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Heteromeric Kir4.1/Kir5.1 potassium channels play key roles in regulating distal tubule potassium sensing and sodium chloride transport. Mutations in KCNJ10 and KCNJ16, encoding Kir4.1 and Kir5.1, respectively, lead to several renal tubulopathies. Given the importance of Kir4.1/Kir5.1 in maintenance of renal salt and water homeostasis, we sought to develop pharmacological tools for exploring its physiology, druggability, and therapeutic potential.


Fluorescence-based thallium flux assays were used for high-throughput screening (HTS) of small-molecule libraries for novel Kir4/1/Kir5.1 activators. Whole-cell and cell-attached patch clamp techniques were used to characterize effects of VU0493206 on Kir4.1/Kir5.1 channel activity. A voltage-sensitive dye was used to characterize effects of VU0493206 on mCCDCl1 cell membrane potential.


We performed a HTS of 87,475 compounds for novel channel modulators, leading to the discovery of 427 inhibitors and 107 activators of heteromeric Kir4.1/Kir5.1 channels. Here, we report the discovery and characterization of VU0493206, the first small-molecule activator of Kir4.1/Kir5.1 channels. In whole-cell patch clamp experiments, VU0493206 activates Kir4.1/Kir5.1-mediated currents by approximately 600% at -120 mV with an EC50 of 11 µM. Cell-attached patch clamp recordings indicates activation is mediated by an increase in single channel current amplitude and number of open channels. VU0493206 hyperpolarizes the membrane potential of mCCDCl1 renal epithelial cells, consistent with activation of endogenously expressed Kir4.1/Kir5.1 channels. At doses up to 30 µM, VU0493206 is selective for Kir4.1/Kir5.1 over 11 other members of the Kir channel family. Depletion of plasmalemmal PIP2 and mutation of PIP2-binding sites on the channel prevents Kir4.1/Kir5.1 activation by VU0493206. Heteromeric channels carrying a novel loss-of-function mutation in Kir5.1 (T64I) are activated by VU0493206, suggesting that some disease-causing mutations in Kir4.1/Kir5.1 may be rescued with activators.


We anticipate that VU0493206 and other small-molecule modulators will be useful for exploring the integrative physiology and therapeutic potential of Kir4.1/Kir5.1 heteromeric channels.


  • NIDDK Support