Widespread brain receptor hides surprising mechanism of action

Date:
April 20, 2022
Source:
Columbia University Irving Medical Center
Summary:
One of the most important molecules in the brain doesn't work
quite the way scientists thought it did, according to new work.



FULL STORY ==========================================================================
One of the most important molecules in the brain doesn't work quite
the way scientists thought it did, according to new work by researchers
at Columbia University Vagelos College of Physicians and Surgeons and
Carnegie Mellon University.


==========================================================================
The results, published April 20 in Nature,may aid the development of a
new generation of more effective neurological and psychiatric therapies
with fewer side effects.

The new research takes a close look at glutamate, the most prevalent neurotransmitter in the brain. Glutamate binds to receptors on brain
cells, which opens a channel into the cell, allowing ions to pass through
to propagate an electrical signal.

"The way the brain works is through communication between neurons,
and these are the main receptors which allow this communication," says Alexander Sobolevsky, PhD, associate professor of biochemistry and
molecular biophysics at Columbia and senior author on the paper.

Each receptor can bind up to four molecules of glutamate and produce four different levels of conductivity. Previous studies had linked binding
to conductivity in a simple stepwise fashion, in which binding each
additional glutamate molecule increased the conductivity another step.

While that explanation made sense, nobody had looked closely enough to
confirm it. In the new work, the investigators combined a technique
called cryo- electron microscopy with sophisticated data analysis to
reveal the first detailed pictures of glutamate binding to its receptors.

"We actually carried out experiments in the conditions where we see
all these intermediates, one glutamate and then two glutamates, three glutamates, and then it binds all four," says Sobolevsky.

These images reveal that glutamate binds to the subunits of its receptor
only in specific patterns. That overturns the prevailing view that each
subunit binds glutamate independently and points toward new levels of complexity in neuronal signaling and drug responses.

Instead of straightforward stepwise transitions, Sobolevsky and his
colleagues found that a glutamate molecule must bind to one of two
specific receptor subunits before any glutamates can bind to the other
two subunits. In addition, the conductivity levels of the receptor
didn't correlate directly to the number of glutamates bound to it;
a receptor could have two or more glutamates attached but still only
reach the first level of conductivity.

The results open an entirely new line of investigation, and the team
is now probing how different accessory molecules on neurons affect
the interaction.

Learning more about the glutamate receptors' specific activation states
may aid the development of better drugs for conditions that involve
glutamate receptors, such as depression, dementia, Parkinson's disease, epilepsy, and stroke.

Video: https://youtu.be/IeQZTFMz5ek The study was supported by the
National Institutes of Health (R01 CA206573, R01 NS083660, R01 NS107253,
R01 AR078814, R01 GM128195, and R01 AG065594) and the National Science Foundation (1818086, 1818213, and 1563291).


========================================================================== Story Source: Materials provided by
Columbia_University_Irving_Medical_Center. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Maria V. Yelshanskaya, Dhilon S. Patel, Christopher M. Kottke,
Maria G.

Kurnikova, Alexander I. Sobolevsky. Opening of glutamate
receptor channel to subconductance levels. Nature, 2022; DOI:
10.1038/s41586-022-04637-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220420170503.htm

--- up 7 weeks, 2 days, 10 hours, 51 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)