Melatonin receptor research could point to a better night's sleep

April 24, 2019

A third of all Americans have difficulty sleeping, and many of them turn to melatonin supplements to catch some Zs. However, scientists don’t fully understand melatonin’s role in the biological clock, which has made it difficult to develop drugs for sleep disorders without several side effects.

Now, an international team of scientists, including faculty from Arizona State University’s Biodesign Institute and Department of Physics, has shed much-needed light on melatonin’s effects, opening the door to the development of new drugs for sleep disorders and other health issues affected by melatonin. They developed 3D models of the tiny antennae — called receptors — on the surface of cells that synchronize the body’s internal clock with the day and night cycle. Melatonin Scientists now have 3D models of two melatonin cell receptors that could lead to better treatments for sleep disorders. Download Full Image

“Our goal is to provide the structural information to other researchers who can use it for designing new drug compounds or to study mutations of these receptors in patients,” said corresponding author Vadim Cherezov, a scientist at the Bridge Institute at USC Michelson Center for Convergent Bioscience.

Creating the 3D maps of the two melatonin receptors, MT1 and MT2, is critical for understanding how the biological clock works. Scientists can use this information to design drug molecules that bind to the melatonin receptors and monitor the potential effects. The benefits could go beyond improving sleep.

“This data will help us design drugs that interact only with these receptors, with the hope we can treat a variety of conditions including diabetes, cancers and sleep disorders, in a more targeted way,” said Bryan L. Roth, pharmacology professor at the UNC School of Medicine.

The findings on the melatonin receptors were published in two letters on Wednesday, April 24, in the journal Nature.

Melatonin comes from the ‘soul’

Melatonin is generated in the center of the brain by the pineal gland, once described by the philosopher Descartes as the “soul” of the brain and body.

Humans respond naturally to daylight changes through the pineal gland, near the hypothalamus. As night falls, the gland produces more melatonin, which then binds to the MT1 and MT2 receptors of the cells. Before dawn, the gland decreases melatonin levels, signaling that it’s time to wake.

MT1 and MT2 are among an estimated 800 receptors in the human body. These receptors, known as G protein-coupled receptors (GPCRs) appear on the surface of a cell. The receptors act as a sort of email inbox, relaying information into the cell to set off a cascade of activity.

About a third of all drugs on the market are designed to bind with GPCRs. Each receptor has a different role in regulating functions in the body, many of which are critical for basic survival, such as hunger and reproductivity. The bulk of these receptors also have some role in the human olfactory system — taste and smell.

Scientists around the world have obtained structures of less than one-tenth of these receptors so far. MT1 and MT2 are among the latest. The MT1 and MT2 receptors are important for multiple processes, including reproduction and even some cancers.

"By comparing the 3D structures of the MT1 and MT2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other — and their roles in the biological clock,” said Wei Liu, a faculty member at the ASU Biodesign Center for Applied Structural Discovery and an assistant professor at the School of Molecular Sciences. “Armed with this knowledge, it becomes easier to design drug-like molecules that will bind to only one receptor or the other, but not both. This selective binding is important as it will minimize unwanted side-effects."

The structures of both receptors were obtained using a laser, called the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory, which uses X-rays to take stop-action pictures of the receptor atoms and molecules in motion.

“Due to the tiny size of the crystals, it wouldn’t have been possible to make these measurements anywhere other than LCLS,” said co-author Alex Batyuk, a scientist at SLAC National Accelerator Laboratory. “Because of the extreme brightness and short pulse duration of LCLS, we were able to collect hundreds of thousands of images of the crystals to figure out the three-dimensional structure of these receptors."

About the study

The research is the result of a collaboration among scientists at USC, Arizona State University’s Biodesign Institute and Department of Physics, SLAC National Accelerator Laboratory, University of Buffalo, University of North Carolina and the Université de Lille in France.

The work was supported by National Institutes of Health grants (R35 GM127086, R21 DA042298, R01 GM124152, and U24DK116195), the NIMH Psychoactive Drug Screening Program (contract F31-NS093917), the National Science Foundation BioXFEL Science and Technology Center 1231306, EMBO ALTF 677-2014, HFSP long-term fellowship LT000046/2014-L, and a postdoctoral fellowship from the Swedish Research Council, SLAC, supported by the U.S. Department of Energy’s Office of Science via contract DE-AC02-76SF00515.

New ASU School of Earth and Space Exploration director selected

April 24, 2019

Professor and cosmochemist Meenakshi Wadhwa has been selected as the new director for Arizona State University's School of Earth and Space Exploration beginning in July of this year. 

“Professor Wadhwa is an outstanding scholar with a proven record of scientific leadership, particularly at NASA,” said Nancy Gonzales, dean of natural sciences in The College of Liberal Arts and Sciences. “She is well positioned to lead the school in becoming a global leader in Earth and space science and education.” Professor Meenakshi Wadhwa, ASU School of Earth and Space Exploration. Photo Courtesy: ASU Download Full Image

Wadhwa has been with ASU since 2006 as the director of the Center for Meteorite Studies and professor in the School of Earth and Space Exploration. She is best known for developing novel methodologies for high precision isotope analyses related to her research in the time scales and processes involved in the formation and evolution of the solar system.

“I’m incredibly energized by the great momentum that we have gained over the last 12 years under the leadership of outstanding directors,” Wadhwa said. “It is truly an honor to have the opportunity to lead this groundbreaking and innovative school to even greater success.”

Wadhwa received her doctorate from Washington University in St. Louis and was a postdoctoral researcher at the University of California at San Diego and then curator at the Field Museum in Chicago before moving to ASU.

She is a recipient of the Fulbright-Nehru Academic and Professional Excellence Award (2015), the Guggenheim Fellowship (2005) and the Nier Prize of the Meteoritical Society (2000). Asteroid 8356 has also been named “8356 Wadhwa” in recognition of her contributions to meteoritics and planetary science.

“Professor Wadhwa is rare among academics for being both an international-status scientist and a person with deep training in leadership. We are so fortunate to have her step into leadership of this wonderful school, with her skills and her existing dedication to the school and its vision,” said outgoing school director Lindy Elkins-Tanton, who will be staying at ASU to co-chair the Interplanetary Initiative and lead the NASA Psyche Mission, as well continuing as a faculty member in the School of Earth and Space Exploration.

“I’m excited about our future,” Wadhwa said, “and I am looking forward to working with the entire community in the School of Earth and Space Exploration to enhance the success of our students and on growing our impact locally, nationally and globally.”

About the school

Established in 2006, ASU’s School of Earth and Space Exploration is committed to high-impact scientific discovery, asking important questions with deep consequences and exploring the great unknowns of the Earth, our solar system and the universe beyond. This interdisciplinary school combines the strengths of science, engineering and education to set the stage for a new era of exploration.

Karin Valentine

Media Relations & Marketing manager, School of Earth and Space Exploration