While studying the peripheral nerves of the Drosophila, aka the fruit fly, Rice doctoral student Eric Howlett discovered an unanticipated connection between glutamate – an amino acid and neurotransmitter in much of the food we eat – and phosphoinositide 3-kinase (PI3K), an enzyme that, Howlett found, regulates the activity of neurons.
Howlett and his colleagues, graduate student Curtis Chun-Jen Lin, research technician William Lavery and Michael Stern, a professor of biochemistry and cell biology, discovered that negative feedback mediated by PI3K regulates the excitability of neurons, an issue in a number of ailments that include neurofibromatosis, and that a mutation in a glutamate receptor gene common to both the fruit fly and humans has the ability to disrupt that regulatory mechanism.
Howlett found the Drosophila’s metabotropic glutamate receptor (DmGluRA) gene, when mutated, increased the excitability of the neuron by preventing PI3K from doing its job.
Published online by the Public Library of Science Genetics, the study is the culmination of four years of work that built upon research by Marie-Laure Parmentier and her team at the University of Montpelier, France, to connect glutamate to regulatory functions in the fruit fly.
“As science often goes, we didn’t set out with this hypothesis,” said Howlett, who began the project on funding obtained by Stern from the Department of Defense to study neurofibromatosis. “This all came about as a control for a completely different experiment, and we said, ‘Wow, this is some interesting stuff.’”
What he saw was that the overexpression of PI3K in motor neurons had a dramatic effect. “I noticed under the scope that these nerves were really big, and electrophysiologically, they were really slow. That wasn’t what I expected, and it set me on a path of trying to find out what was going on.”
Howlett’s breakthrough was identifying the negative feedback loop that acts to maintain neuronal excitability at normal levels. “What we found was that glutamate, which is released due to neuronal activity, feeds back onto metabotropic glutamate receptors on the same neurons that released it in the first place. This leads to the activation of PI3K and ultimately to the dampening of the amount of glutamate that is released.” Without that regulation, he said, things inside the cell can go terribly wrong.
“He put his heart and soul into this,” said Stern of Howlett’s exploration of the neuronal chain. “He was working on PI3K because that has a key role in neurofibromatosis. The Department of Defense is very interested in how PI3K is regulated in the nervous system because of its role in tumor formation.”
Discovering the negative feedback loop that keeps neurons stable was key, said Stern, but not the end of the investigation. “We know that glutamate activates mGluR and PI3K, but we don’t know how,” he said. “There are almost certainly a number of intermediates that remain to be identified, and we have several candidates we’re looking into.
“We’re finding a mechanistic link among these molecules that hadn’t been previously appreciated,” Stern said.
“Obviously the next step would be to test whether these same molecules are playing similar roles in mammalian neurons,” said Howlett, who will leave Rice in the spring to pursue postdoctoral cancer research at Virginia Commonwealth University. A native Houstonian, he earned his bachelor’s in biology at the University of Houston-Clear Lake.
Howlett said mGluRs had already been targeted in possible treatments for schizophrenia, epilepsy and other “excitability” diseases, so it’s not a stretch to think his research could lead to even more strategies in treating neurological ailments.
“Actually, all of the molecules involved in our model have been implicated in one way or another with neurological diseases, but no one has been able to link them together into a coherent explanation of the diseases,” he said. “Our model provides a novel framework that could really go a long way toward doing that.”
The paper can be found at: www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1000277.
David Ruth | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy