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.

Background

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: GABA_A and GABA_B. GABA_B receptors respond relatively slower to GABA signaling, but have prolonged effects.

The findings

The researchers used cryo-electron microscopy to grab snapshots of the GABA_B 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 GABA_B receptor is activated by a sequence of three critical events.

The bigger picture

Defects in the GABA_B receptor are closely related to neurological and psychiatric disorders, including epilepsy, addiction, depression and schizophrenia. The GABA_B structure helps researchers understand how the receptor maintains its inactive state and serves as an invaluable template for future drug design efforts.