For the first time, scientists have visualized a new class of molecular gates
that maintain pH balance within brain cells, a critical function that keeps
cells alive and helps prevent stroke and other brain injuries.
These gates, called proton-activated chloride channels (PAC), nest within
cell membranes and regulate the passage of small molecules called chloride
ions into and out of cells. This allows cells to sense and respond to their
environment.
"Proton-activated chloride channels have only recently been described but
they are critical for cell survival, particularly in the brain," said Wei
Lü, Ph.D., a Van Andel Institute assistant professor and co-corresponding
author of the study, which was published today in Nature. "Our new images,
coupled with our findings into how these channels work, provide much-needed
molecular blueprints that will help answer long-standing questions in the
field and provide new insights into how these channels may be
therapeutically targeted in disease."
The images reveal a wedding bouquet-like structure, with parts that change
configuration in response to environmental pH. When pH shifts from alkaline
to acidic, a key pH sensor moves from its "resting" location and is inserted
in an "acidic pocket," which signals that the gate allowing ions in and out
of the cell should be open. This specific mechanism has never before been
described.
This study is a collaboration between the Lü Lab at Van Andel Institute and
a group led by Zhaozhu Qiu, Ph.D., an assistant professor at Johns Hopkins
University School of Medicine and co-corresponding author of the paper. The
Johns Hopkins team first reported the discovery of PAC in Science last year.
Solving PAC structures are another important, early step toward an
understanding that may one day impact human health.
Reference:
Zheng Ruan, James Osei-Owusu, Juan Du, Zhaozhu Qiu, Wei Lü. Structures and
pH-sensing mechanism of the proton-activated chloride channel. Nature, 2020;
DOI:
10.1038/s41586-020-2875-7
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