Rh proteins act as gas channels that help speed the transfer of carbon dioxide (CO2) in and out of red blood cells. CO2 can also pass through the cell membrane unaided (above right), but not quickly enough, said UC Berkeley researchers. (Image by Barbara Alonso)
By Sarah Yang, Media Relations | 25 May 2005
BERKELEY – Labels marking bags of donated blood throughout the world contain information about the presence of a Rhesus (Rh) antigen, a protein found on the membranes of human red blood cells. Yet, despite the Rh protein’s importance in blood transfusion and the problems it can cause between Rh negative mothers and their Rh positive fetuses, its biological role has remained largely unresolved since its discovery 65 years ago.
But a new study, led by biologists at the University of California, Berkeley, and due to be published June 22 in the journal Genetics, may help clarify the mystery by giving additional evidence that the Rh protein serves as a gas channel for carbon dioxide (CO2).
Rh proteins act as gas channels that help speed the transfer of carbon dioxide (CO2) in and out of red blood cells. CO2 can also pass through the cell membrane unaided (above right), but not quickly enough, said UC Berkeley researchers. (Image by Barbara Alonso) |
The study’s conclusions, the researchers said, will lead to new directions in human and animal physiology research, as well as generate lively debate among biochemists and hematologists.
“This has implications for understanding how humans breathe, how we control the acidity (pH) of various fluids in our bodies and how our kidneys function, all of which rely upon movement of CO2 across cell membranes,” said Sydney Kustu, professor of plant and microbial biology at UC Berkeley’s College of Natural Resources and principal investigator of the study.
Kustu noted that scientists had long doubted the presence of protein channels for CO2 or any gases. This is because gases typically have no trouble crossing cell membranes unaided, so it was not suspected that the Rh protein would play such a role.
But among gases, carbon dioxide (CO2) and ammonia (NH3) are exceptional, the researchers explained. They both dissolve readily in water, which can slow their passage across oily membranes.
Recent evidence indicates that ammonium/methylammonium transporter (Amt) proteins act as gas channels for NH3. Unlike active transporters, channels allow multiple molecules of gas to move through at the same time, an important distinction for gases that need to move across membranes quickly.
Until a few years ago, scientists thought that Amt handled the charged ion for ammonia (NH4+), which is the major form found in water. They also believed Amt was an active transporter and used energy to move the ion molecules in or out of cells against a gradient.
Notably, Rh and Amt proteins are more closely related to each other than any other proteins. Because of this, many scientists have suggested that Rh proteins also function as active transporters for charged ammonium ions.
“Our research corrects that assumption by showing that Amt proteins are working with ammonia gas, and Rh proteins are working with carbon dioxide” said Kwang-Seo Kim, a research specialist at the Kustu Lab and lead author of the paper. “Other experiments that suggest that Rh proteins transport ammonium ion have involved cloning Rh genes into microorganisms or cells that do not have them naturally.”
The researchers reached their conclusions by studying the humble green alga, Chlamydomonas reinhardtii, one of the few microorganisms known to have both Rh and Amt proteins. Amt proteins are widespread among microbes and plants, which use ammonia as the preferred source of nitrogen, a critical nutrient.
In contrast, Rh proteins are rare among microbes, yet common in vertebrates. Ammonia is toxic to vertebrates and, not surprisingly, Amt proteins are absent in this class of animals.
The researchers suggested that green algae have Rh proteins because they thrive in aquatic environments with high concentrations of CO2. Algae use sunlight energy to capture CO2 by photosynthesis.
Kustu and other researchers had previously shown that expression of the Rh gene in C. reinhardtii was high for cells grown in air supplemented with 3 percent CO2, about 100 times the concentration normally found in air. When the algae were grown in air, expression of the Rh gene was low.
They’ve also found that strains of C. reinhardtii in which the Rh protein was missing did not grow well in environments with high levels of carbon dioxide, suggesting that Rh was necessary for the algae’s ability to benefit from high CO2 levels.
In this new study, Kustu and her research team isolated strains of C. reinhardtii in which an Amt gene was inactivated. They found a 90 percent reduction in uptake of the ammonia analogue methylamine in those mutated strains of green algae. In contrast, strains of the green algae in which the Rh gene was inactivated remained sensitive to methylamine and showed no deficiencies in the uptake of the ammonia analogue.
“This paper is the last piece in a puzzle about Amt and Rh proteins,” said William Inwood, a research specialist in the Kustu Lab and the senior author of the study. “We’ve provided strong evidence that the substrate for the Amt protein is ammonia, while the substrate for the Rh protein is carbon dioxide within the same organism.”
What do Rh proteins in green algae have to do with Rh proteins in humans? “It turns out that if you know the biochemical function of a protein, you know it,” said Kustu. “A protein’s biochemical function does not change from organism to organism.”
Kustu also notes that the Amt channels are needed when ammonia is available in low concentrations, while the Rh channels kick into gear at high concentrations of carbon dioxide like those found in humans. The concentration of CO2 in human breath is as high as 5 percent.
The Rh protein’s role in CO2 transport makes sense given its location on the surface of red blood cells, the researchers said. “Red blood cells need to transport CO2 from body tissue out through the capillaries of the lungs very quickly, and the Rh protein in blood cells is about speed,” said Kustu.
Scientists have long taken an interest in the role of Rh protein in the shape and flexibility of red blood cells. The red cells of people who lack all Rh antigens, an extremely rare condition, are misshapen and easily ruptured. It is believed that the Rh protein helps to maintain the flexible, flattened shape of red blood cells. “This structural role is secondary to its original function as a gas channel for CO2,” said Kustu. “It seems to be a newly evolving role that increases gas transport in red cells by increasing their surface area.”
In addition to being present in red blood cells, Rh proteins are found in a variety of human organs including seminal vesicles and the kidney and brain. “Their location points to the multiple roles Rh proteins play in human physiology,” said Kustu. “All this is to say that there is more to Rh proteins than previously thought, and they deserve more research. Studying them will lead in many interesting directions.”
Other co-authors of the paper are Eithne Field, a former manager at the Kustu Lab at UC Berkeley; Natalie King, a post-doctoral researcher at the State University of New York at Buffalo’s Department of Microbiology; and Takuro Yaoi, a scientist at Panomics, a research technology firm in Redwood City.
The research was funded by grants from the National Institutes of Health and from Syngenta’s Torrey Mesa Research Institute, which closed in 2003.
Source:
New research provides evidence that Rh proteins act as CO2 gas channels
More details:
Oxygen shortage and larger impact from toxic gases and acids
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Mike:
I have just re-read this. I see it as highly significant..but will not speculate for the moment.
Sydney Kustu was an extraordinary scientist at UC Berkeley (across the Bary from where I live), though she ended up taking her own life.
https://plantandmicrobiology.berkeley.edu/sites/default/files/users/SydneyKustu%20%281%29.pdf
Others have speculated that this may explain the genesis of the RH gene de-activation…which requires acceptance of the idea that environment can change genes. I have no trouble with that concept, but am very curious about the specifics of such interactions.
I am looking up her studies:
“The Rhnull syndrome in humans, which is very rare (<1/106), is associated with pronounced morphological and biochemical abnormalities of the red cell (2-4, 6, 9, 48-50). These include different degrees of stomatocytosis (bending to form a mouth-like opening), increased osmotic fragility, altered phospholipid asymmetry, altered cell volume, defective cation fluxes, and elevated Na+/K+ ATPase activity. Differences in the accumulation of a weak base such as methylammonium could be the consequence of one or more of these pleiotropic secondary abnormalities rather than a direct result of loss of the primary function of the Rh blood group substance."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419684/
Besides the subject, but very strange:
“On March 18, 2014, Sydney committed suicide on her 71st birthday, by swallowing the poisonous chemical, sodium azide. She was found by a maid in a room at the Berkeley City Club, along with a note to warn authorities about the dangerous substance having been used in the room, as well as a note with her personal information such as her laptop passcode.[5] A bottle of research-grade sodium azide, likely obtained from her former laboratory, had been left on a table with its lid tightly secured.[6] The unusual nature of her suicide prompted a major emergency response operation to evacuate the landmarked Julia Morgan-designed building. Sodium azide is a commonly-used research chemical, used as a biocide to prevent unwanted bacterial growth in stock chemicals, as well as an inhibitor of cytochrome oxidase for studying the influence of oxidative respiration in gram-negative bacteria.”
From Wikipedia
Are you saying that the RH gene deactivation means that the RH gene will be deactivated? Or that the RH negatives will be deactivated ? This article appears to suggest that RH negs cannot clear carbon dioxide the way that positives can. Hence if CO2 somehow increased in environment, would that not affect the RH negs? And not affect the RH positives?
very interesting subject – i’m wondering if CO/carbon monoxide sensitivity or CO elimination is also affected. i have been very sensitive to CO gas at least since my early 20’s. automobile exhaust leaks and poorly venting furnaces & such annoy the hell out of me, plus they make me sick (headaches & such). i seem to be much more sensitive to CO than my parents and brother. they are all Rh positive.
I agree and have the same symptoms and am RH neg
That seems very likely to me. I think that it is at least a partial explanation of my atrial fibrillation, which required ablation surgery on the pulmonary veins responsible for the evacuation of de-oxygenated blood from the cardiovascular system.
All of this is a big step forwards in understanding the “mechanics” involved….rather than looking at the
primary consequences (mostly transfusion and mother/child incompatibilities.) It may help figure out secondary consequences as well.
Are you RH neg?
Yes…CDE Rh Neg
Do you have that study handy?
Try this link….
https://www.genetics.org/content/170/2/631
One more quick comment. I have found that controlled deep breathing can reduce the fibrillations in my
pulmonary arteries as well as my blood pressure (by about 10 points). This fits very tidily with the CO2 research findings.
I have found this interesting being an RH negative. Since childhood ( I am now over 70) I have struggled with periods of excessive yawning. The doctors just told me to get some fresh air and to breath deeper, but that did not change anything. It has only been recently that I have found out that I have periods of low oxygen levels. When this yawning fits occur I appear not to be gasping for oxygen but exhaling heavily to rid my body of CO2. Once levels appear to be balanced I am back to normal again.
I am also now using a CPAP machine which is helping my oxygen levels at night, but still have yawning attacks regularly.
How elevated are you located?
My current Elevation: 126m / 413feet.
However this started when I was in my teens and at that time I lived close to the sea.
I too have extensive bouts of yawning, I am so glad to have noticed/read all this (1086 ft elevation here). Happens to me 2 or more times in 12 hours, morning/afternoon and in the evening. I yawn SO MANY times I have tears streaming from my eyes. Never occurred to me I could be releasing CO2 rather than trying to gain oxygen. Intend to delve deeper into this!
At least we are not alone. Did you used to faint a lot when you were younger? I used to faint regularly especially in crowds, trains and when I was pregnant. The CO2 connection is only an observation. Nothing has ever been confirmed as causing the yawning. Medical doctors have only made suggestions.
no fainting for me, just lots of yawning (right now actually, ha). Has been with me my whole life and I always found it to be odd how much of it i do