Ion Channels & Altitude
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Near the Mt. Everest peak, 8200 meters above sea level, the low pressure and oxygen content of the air will make climbers feel light-headed and drunk almost immediately. Humans don’t thrive at such high altitudes. Not far beneath Mt. Everest, at an altitude of nearly 6000 meters, 4.5 million people reside on the Qinghai-Tibetan plateau of China. Whereas most people that visit or reside in near mountain tops are prone to altitude sickness, the incidence of altitude sickness is rare amongst Tibetans. It has been proposed that the ability of Tibetans to thrive in such high altitudes may be the result of genetic adaptations to hypoxic conditions [2].
In “Life at the Extremes,” a book written by Frances Ashcroft, there is a chapter detailing life at extreme heights. There are details such as mountain sickness, barometric pressure, and acclimatization at high altitudes. The chapter states that the highest altitude that humans live is not far beneath Mount Everest’s peak of 8200 meters [1]. A little below that, at anywhere from 3500 to 6000 meters, the Tibetan population of over 4.5 million people reside on a plateau in China called the Qinghai-Tibetan plateau [2].
In a recent article entitled PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel (PMID 31023925), researchers from Qui lab at Johns Hopkins present data suggesting that mutations in TMEM206 may help residents of the Qinghai-Tibetan plateau thrive at altitude [3]. Based of this genetic difference, the authors proposed that PAC could play a role in adaptation to hypoxic conditions. This begs the question: What is PAC?
The proton-activated chloride channel (PAC) is found in diverse tissue types [3]. Although PAC-currents where known prior to this paper, the genes that gave rise to this channel were unknown. Using an siRNA screen, TMEM206 was identified as the gene that encoded for the PAC channel [3]. After the gene was identified, the researchers used various experiments characterize the PAC channels including CRISPR-Cas9 to delete the channel from various cells and whole-cell patch-clamping to record PAC-conducted currents [3]. They found that when acidic solutions were applied, these PAC channels were more active, and conducted larger currents. Moreover, they hypothesized that the PAC channels were directly regulated protons in regulation of their gating [3].
To test whether the proton-activated channel was able to facilitate chloride, 4,4’diisothiocyano-2,2’stilbenedisulfonic acid (DIDS) was applied, a known chloride current inhibitor. Since it was inhibited, further confirmation was needed, to confirm that PAC is a chloride channel. Recordings were performed in a solution that replaced extracellular chloride with gluconate, an impermeable anion. With a lack of extracellular chloride, the currents ceased, indicating that PAC is a chloride channel [3].
Since it was known that PAC utilizes both protons and chloride, the next step was to confirm that PAC was directly associated with the chloride channel, and not just a regulatory molecule. Through generating substitutions in different amino acids and applying inhibitors and reducing agents, it was confirmed that PAC is an integral component of the channel, and not just a regulatory element [3].
Yang et al. concluded the paper by examining PAC knockouts in mice, and saw that mice with the knockouts has less severe ischemic brain injury, and had improved neurological scores when exposed to acidosis-mediated neuronal toxicity. This indicates that PAC may be a potential target for drugs to treat strokes and other acidosis-related diseases [3].
The information in the paper PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel provides evidence that PAC is not only a possible target for stroke, but also is directly related to the gene changes in the Tibetan people, and is also seen at higher rates of natural selection in pigs that are adapted to live in high altitudes. There is still a lot more to be learned about PAC, and furthering the knowledge about it could possibly lead to a way to allow people to live their life in more extremes, like the Tibetan people of China.
Post written by Kayla Komondor and Anne Carlson
Ashcroft, F. (2001). Life at the Extremes. Berkeley and Los Angeles: HarperCollins Publishers, pp.7-40.
Wu, T. (2001). The Qinghai–Tibetan Plateau: How High Do Tibetans Live? High Altitude Medicine & Biology, 2(4), 489–499. doi: 10.1089/152702901753397054
Yang, J., Chen, J., del Carmen Vitery, M., Osei-Owusu, J., Chu, J., Yu, H., Sun, S. and Qiu, Z. (2019). PAC, an evolutionarily conserved membrane protein, is a proton-activated chloride channel. Science, 364(6438), pp.395-399.