CryoEM Reveals A Molecular “Latch” that Controls Neuron Activity
Scientists at the Vagelos College of Physicians and Surgeons at Columbia University Irving Medical Center have captured a near complete snapshot of the gamma-aminobutyric acid (GABA) B receptor, a protein that regulates neuronal activity.
Our brains process information and give executive orders through pathways that balance excitation and inhibition of neuronal circuits. GABA is an inhibitory neuromodulator, which means that it reduces the activity of neurons. There are two known classes of GABA receptors: GABAA and GABAB. GABAB receptors respond relatively slower to GABA signaling, but have prolonged effects.
The researchers used cryo-electron microscopy to grab snapshots of the GABAB receptor. The high-resolution structure shows how different subunits of the receptor are held together, with a unique “latch” locking the protein in an inactive state. The structure also reveals that a calcium ion and two phospholipids could play key roles in the receptor’s function. Combined with the findings of a previous study, the researchers suggest that the GABAB receptor is activated by a sequence of three critical events.
The bigger picture
Defects in the GABAB receptor are closely related to neurological and psychiatric disorders, including epilepsy, addiction, depression and schizophrenia. The GABAB structure helps researchers understand how the receptor maintains its inactive state and serves as an invaluable template for future drug design efforts.
The paper is published in Nature and is titled “Structure of human GABAB receptor in an inactive state.”
The paper's corresponding authors—all from Columbia University Vagelos College of Physicians and Surgeons–are:
Oliver B. Clarke, PhD, assistant professor of physiology (in the Department of Anesthesiology),
Joachim Frank, PhD, professor of biochemistry & molecular biophysics, and
Qing R. Fan, PhD, associate professor of pharmacology and of pathology & cell biology.
Other Columbia authors are Jinseo Park, Ziao Fu, Aurel Frangaj, Jonathan Liu, Lidia Mosyak, Vesna N. Slavkovich, Kimberly M. Ray, Baohua Cao, Yong Geng, Hao Zuo, Robert Grassucci, Zheng Liu, Xin Lin, Rajesh K. Soni, Jonathan A. Javitch, Wayne A. Hendrickson, Matthias Quick, and Joseph Graziano. Other authors: Tong Shen (UC Davis), Jaume Taura (Mount Sinai), Yongjun Kou (SIMM), Shaoxia Chen (MRC), Justin P. Williams, William J. Rice (SEMC), Edward T. Eng (SEMC), Rick K. Huang (Janelia Farm), Brian Kloss (COMPPA), Zhiheng Yu (Janelia Farm), Paul A. Slesinger (Mount Sinai), Hongtao Yu (UT Southwestern), and Oliver Fiehn (UC Davis).
The study was supported by NIH grants R01GM088454, R01GM125801, R01GM107462, P41GM116799, and U2C ES030158.
The authors declare no financial or other conflicts of interest.