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Abstract: FR-PO1024

pH-Dependent Channel Formation by APOL1: Gateway to Toxicity?

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic


  • Thomson, Russell P., Hunter College, City University of New York, New York, New York, United States
  • Giovinazzo, Joseph A., Hunter College, City University of New York, New York, New York, United States
  • Schaub, Charles Michael, The Graduate Center of the City University of New York and Hunter College CUNY, New York, New York, United States
  • Finkelstein, Alan, Albert Einstein College of Medicine, New York, New York, United States
  • Raper, Jayne, Hunter College, City University of New York, New York, New York, United States

African variants of apolipoprotein L-I (APOL1) are strongly associated with kidney disease among African Americans. APOL1 variants are cytotoxic when expressed in human cells, a property which is associated with the formation of pH-dependent cation fluxes across the plasma membrane. This cation flux is likely mediated by APOL1 itself as recombinant APOL1 forms pH-gated cation-selective channels in planar lipid bilayers that are similarly affected by pH. Here we show that APOL1 of baboons also forms a cation-selective conductance in planar lipid bilayers, but that this conductance is largely unaffected by pH. We identify two human APOL1-specific residues - tyrosine-351 and glutamate-355 - that combine to produce channel closure at acidic pH and opening at neutral pH.


We utilized human-baboon APOL1 chimeras and site-directed mutagenesis to identify residues involved in pH gating. Recombinant proteins were produced in E. coli and incorporated into planar lipid bilayers using established techniques.


Similar to baboon APOL1, a human-baboon APOL1 chimera containing the C-terminal 46 residues of baboon APOL1 produced channels that remained open at acidic, as well as neutral pH. This effect could be entirely replicated with the single change of tyrosine-351 for its baboon-specific counterpart glycine, but was only partially recapitulated by the more conservative tyrosine-351 for phenylalanine substitution. A single substitution of human APOL1 glutamate-355 for the uncharged glutamine also abrogated pH gating.


We propose that under acidic conditions the bulky side-chain of Tyr-351 is positioned to effect channel closure. Upon pH neutralization Glu-355 becomes negatively charged, allowing for displacement of Tyr-351 and for channel opening to occur. Investigations are currently underway to determine if mutation of channel gating behavior affects the toxicity of APOL1 when expressed in human cells.