NIH researchers gain better understanding of how neuropeptide hormones trigger chemical reactions in cells
Many hormones and neurotransmitters work by binding to receptors on a cell's exterior surface. This activates receptors causing them to twist, turn and spark chemical reactions inside cells. NIH scientists used atomic level images to show how the neuropeptide hormone neurotensin might activate its receptors. Their description is the first of its kind for a neuropeptide-binding G protein-coupled receptor (GPCR), a class of receptors involved in a wide range of disorders and the target of many drugs.
"G protein-coupled receptors are found throughout the body. Knowing how they work should help scientists devise better treatments," said Reinhard Grisshammer, Ph.D., an investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in Nature Communications.
Neurotensin is thought to be involved in Parkinson's disease, schizophrenia, temperature regulation, pain, and cancer cell growth. Previously, Dr. Grisshammer and his colleagues showed how neurotensin binds to the part of its receptor located on a cell's surface. In this study, they demonstrated how binding changes the structure of the rest of the receptor, which passes through a cell's membrane and into its interior. There neurotensin receptors activate G proteins, a group of molecules inside cells that controls a series of chemical chain reactions.
For these experiments, scientists shot X-rays at crystallized neurotensin receptor molecules. Making crystals of receptors that activate G proteins is difficult. In most studies, scientists have investigated inactive receptors.
"The receptor we crystallized is very close to the active form found in nature," said Dr. Grisshammer. "We may have the first picture of a peptide-binding G protein-coupled receptor just before it engages with the G protein."
To achieve their results, the scientists made multiple genetic modifications to a less active version of the neurotensin receptor they had used before. Experiments performed in test tubes showed that mixing the receptor with neurotensin sparked the G protein reactions for which the scientists were looking.
When the scientists looked at the structure of the new crystals, they discovered how binding of neurotensin to the receptor caused critical parts of the receptor located below a cell's surface to change shape. In particular, they saw that a region in the middle of the receptor dropped like a draw bridge to link the neurotensin binding site to parts of the receptor found inside cells that are important for G protein activation. The scientists concluded that this change may prepare the receptor for activating G proteins.
"For years scientists have made educated guesses about how peptide receptors work. Now we may finally know," said Dr. Grisshammer.
His lab plans to continue its work in order to fully understand how neurotensin and other G protein-coupled receptors translate messages delivered by neuropeptides into reactions inside cells.
This work was funded by the NINDS Division of Intramural Research.
References: Krumm et al. "Structural prerequisites for G-protein activation by the neurotensin receptor," Nature Communications, July 24, 2015. DOI: 10.1038/NCOMMS8895
For more information, please visit: neuroscience.nih.gov/ninds/Home.aspx
The NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.
Christopher G. Thomas | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences