New study explains salt transport mechanisms and may help treat cystic fibrosis

New study explains salt transport mechanisms and may help treat cystic fibrosis

image: Pablo Artigas, Ph.D., of TTUHSC, and a team of collaborators investigated the structural features of H+/K+ pumps and Na+/K+ pumps that cause them to regulate the passage of salts through membrane barriers.
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Credit: TTUHSC

In a recently published research article, Pablo Artigas, Ph.D., of the Center for Membrane Protein Research at Texas Tech University Health Sciences Center (TTUHSC) School of Medicine’s Department of Cell Physiology and Molecular Biophysics, and a team of collaborators applied functional and structural analyzes to investigate which structural features of the proton/potassium (H+/K+) pumps and sodium/potassium (Na+/K+) cause them to regulate the passage of salts through membrane barriers.

The study “Structure and function of H+/K+ Pump mutants reveal Na+/K+ Pump Mechanisms”, was published in September by Nature Communication. The research team included Artigas and TTUHSC graduate students Victoria C. Young, Ph.D., and Dylan J. Meyer, Ph.D.; Hanayo Nakanishi, Ph.D., Atsunori Oshima, Ph.D., and Kazuhiro Abe, Ph.D., of Nagoya University (Japan); and Tomohiro Nishizawa, Ph.D., of Yokohama (Japan) City University. The study was funded by the National Science Foundation and The CH Foundation.

In every human cell, the Na+/K+ the pump transports two potassium (K+) in the cell and brings out three sodium ions (Na+) ions. Concentration gradients of these ions are required for electrical signaling in the brain, heart, and muscle, as well as for nutrient delivery and regulation of intracellular calcium and proton concentrations in all cell types. The four types of Na+/K+ the pumps are localized in different tissues. Disease mutations in three of these Na+/K+ pumps cause neuromuscular, cognitive, endocrine or cardiovascular disorders.

Two H+/K+ pumps have slightly different ion recognition sites and are expressed on the apical side of many epithelia, where they transport a proton (H+) out of the cell and bring in a potassium (K+) ion. Gastric H+/K+ pump acidifies the stomach and is the target of omeprazole, an antacid. The non-gastric H+/K+ the pump participates in K+ reabsorption and contributes to the acidification of the respiratory tract, an important component of the pathology of cystic fibrosis.

“The two proteins (H+/K+ and Na+/K+ pumps) are about 70% identical, so we looked at what minor differences might be responsible for the difference in selectivity and the number of ions transported,” Artigas explained.

The study determined that the simultaneous replacement of amino acid residues at four locations in the non-gastric H+/K+ pump with those present in the Na+/K+ pump is enough to transform a protein that normally transports one proton for one potassium into a protein that transports three sodium for two potassium, giving new insight into how these proteins select the ions they need to transport.

“To our knowledge, this is the first demonstration of the modification of a protein that exclusively transports H+ transforms into a protein that exclusively transports Na+said Artigas. “We think this could help other people doing similar work with other membrane proteins to engineer a similar change in selectivity between Na+ and H+. We can do it one way, but now we’re trying to do it the other way: come from the Na+/K+ pump to H (not gastric)+/K+ pump.”

The importance of non-gastric H+/K+ pump in the body remains largely unknown, but its inhibition is known to prevent respiratory tract infections in an animal model of cystic fibrosis.

“In addition to transforming one type of protein into another, thanks to our collaborating structural biologists in Japan, we have determined the structure of non-gastric H.+/K+ pump,” Artigas said. “This structure could be used to develop specific inhibitors to effectively treat patients with cystic fibrosis.”

Now that Artigas and his collaborators have successfully converted non-gastric H+/K+ one Na pump+/K+ pump, they attempt several other conversions using gastric H+/K+ and Na+/K+ pumps.

“We still have not succeeded in converting the gastric H+/K+ pump in a Na+/K+ pump or Na+/K+ pump in an H+/K+ pump to fully understand the mechanism of selectivity,” Artigas said. “We will use current and future structures of non-gastric H+/K+pump to try to generate specific inhibitors to help treat patients with cystic fibrosis.

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