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New Insights into Neuronal Communication Discovered by Scientists
A recent study led by researchers at Johns Hopkins Medicine has unveiled new details about how brain cells communicate chemically. The scientists utilized a state-of-the-art microscope to analyze the dynamic process involving glutamate, a key signaling molecule that facilitates the entry of charged particles into neurons. This crucial finding holds promise for the development of medications aimed at addressing various neurological disorders, including epilepsy and specific intellectual disabilities.
The findings were outlined in a report published on March 26 in the journal Nature. The research was financially supported by the National Institutes of Health and was carried out in collaboration with experts at UTHealth Houston.
“Neurons serve as the fundamental building blocks of the brain, and our capacity to interact with our environment and learn relies heavily on the chemical signals exchanged between these cells,” explained Edward Twomey, Ph.D., an assistant professor of biophysics and biophysical chemistry at Johns Hopkins University School of Medicine.
Glutamate, the neurotransmitter at the heart of neuron-to-neuron signaling, is prevalent in the synaptic spaces between neurons. It binds to AMPA receptors on neuronal surfaces, which act as gateways for charged particles. The fluctuations in these charged particles generate electrical impulses that facilitate communication among neurons.
To delve deeper into the atomic movements of AMPA receptors during neuronal signaling, researchers employed a cryo-electron microscope (cryo-EM) at Johns Hopkins University School of Medicine. This high-powered imaging technology allowed scientists to capture detailed snapshots of the receptors as they engaged in their signaling processes.
Although colder temperatures are often preferred for cellular studies, Twomey’s team discovered that AMPA receptor dynamics heightened at physiological temperatures. This increased activity provided enhanced imaging opportunities with cryo-EM.
The scientists meticulously purified AMPA receptors from lab-cultivated human embryonic cells, known for their utility in neuroscience research. After raising the temperature of these receptors to a warm 37 degrees Celsius (98.6 degrees Fahrenheit), they introduced glutamate and then instantaneously flash-froze the samples for cryptic imaging analysis.
By processing over a million cryo-EM images, the researchers observed that glutamate molecules operate like a key, unlocking the AMPA receptor channel and allowing it to open wider. This action is facilitated by the clamshell-like structure of the receptor, which closes around the glutamate, subsequently pulling the channel open.
Twomey’s previous investigations indicated that certain medications, such as perampanel—used in the treatment of epilepsy—function as inhibitors that prevent the AMPA receptor channel from fully opening, thereby moderating excessive neuronal activity associated with the condition.
He emphasized that these new findings could lead to the design of innovative drugs that interact differently with AMPA receptors, potentially either activating or inhibiting these signaling pathways in brain cells.
“Each discovery propels us closer to understanding the fundamental elements that enable brain function,” noted Twomey.
Additional contributors to this research included Anish Kumar Mondal from Johns Hopkins and Elisa Carrillo and Vasanthi Jayaraman from UTHealth Houston.
The study received financial support from the National Institutes of Health, specifically under grants R35GM154904 and R35GM122528, as well as from the Searle Scholars Program and the Diana Helis Henry Medical Research Foundation.
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