Choline, a nutrient vital for brain health, is actively transported from the bloodstream into the brain by a protein. The new discovery is detailed in the journal Nature and funded by the National Institutes of Health (NIH).
“The brain has a particularly high demand for choline, but how it enters the brain has eluded the field for over 50 years,” the researchers noted.
“We need to consume 400-500 milligrams of choline per day to support cell regeneration, gene expression regulation, and for sending signals between neurons,” said lead study author Dr. Rosemary Cater of University of Queensland’s Institute for Molecular Bioscience.
Crossing the blood-brain barrier
“This blood-brain barrier prevents molecules in the blood that are toxic to the brain from entering,” Dr. Cater said. “The brain still needs to absorb nutrients from the blood, so the barrier contains specialized cellular machines—called transporters—that allow specific nutrients such as glucose, omega-3 fatty acids and choline to enter.”
While this barrier is an important line of defense, questions remain.
Up until now, the scientific community has not been able to identify a blood-brain barrier choline transporter or understand its underlying mechanism. Numerous potential transporters have been explored, but researchers found these proteins were not significantly expressed and/or displayed a poor affinity for choline.
The only two genuine human choline transporters discovered to date include the Major Facilitator Superfamily (MFS) transporter FLVCR1 (also called MFSD7B or SLC49A1), which is expressed in most cell types but not highly enriched in brain endothelial cells; and the high-affinity choline transporter ChT (SLC5A7), which is almost exclusively expressed in cholinergic neurons.
FLVCR2 (also known as MFSD7C or SLC49A2) is a close relative of FLVCR1 (55% identity) that is highly and specifically expressed in blood-brain barrier (BBB) endothelial cells throughout development and into adulthood. Research has found that endothelium-expressed FLVCR2 is essential for both normal brain development and cerebral angiogenesis by selectively recognizing and shuttling choline into the brain. But beyond this, nothing is known about FLVCR2's physiological function at the BBB or the identity of its substrate.
Study details
The research team employed a powerful method called cryo-electron microscopy to study FLVCR2 at the atomic level. This allowed them to see the protein's three-dimensional structure and the way that choline molecules bind to FLVCR2's pockets in a manner akin to a lock-and-key process. Utilizing the 3D model, they conducted computer simulations that demonstrated how the protein conforms and reshapes to release choline into the brain.
Results indicated that choline sits in a cavity of FLVCR2 as it travels across the blood-brain barrier and is secured by a cage of protein residues.
“These findings de-orphan FLVCR2 and provide molecular insights into its mechanism of choline transport,” the authors noted. “This is critical information for understanding how to design drugs that mimic choline so that they can be transported by FLVCR2 to reach their site of action within the brain.”
While the findings will help inform the future design of drugs for brain conditions, it also highlights the importance of adequate choline intake to support cognition and optimize the function of the FLVCR2 transporters.
Source: Nature
May 2024 doi.org/10.1038/s41586-024-07326-y
“Structural and molecular basis of choline uptake into the brain by FLVCR2”
Authors: R. Cater et al.