Both internal and external pH sensors can rotate an ion channel's helix to turn ion flow on or off, report Byung-Il Yeh, Chou-Long Huang, and colleagues (University of Texas Southwestern Medical Center, Dallas). “These findings provide the first mechanistic example of how ion channels integrate internal and external signals for function,” says Huang.
The TRPV5 calcium channel is expressed in kidney epithelial tissue where it regulates calcium reabsorption into the blood—an important function since improper calcium control can result in kidney stone disease.
High-acid conditions inhibit TRPV5 function. Huang's group found that when a sensor residue—an intracellular lysine (K607)—binds to protons under low intracellular pH conditions, the protein undergoes a conformational change that causes clockwise rotation of the pore helix. This reduces the pore diameter. Clockwise rotation of the pore helix is also induced when an extracellular glutamate (E522) binds to protons during high extracellular pH conditions. Pore helix rotation ultimately closes the outer selectivity filter of the protein to inhibit calcium flow.
Hence, cross-regulation of the same structure within the protein allows coordinate control of calcium ions under a variety of physiological conditions. This, says Huang, “probably represents a very general mechanism for how channel proteins regulate internal and external signals.”