Researchers report that a protein called filamin A is responsible for guiding receptors to their correct places in brain neurons. These receptors control brain activity in response to GABA, the main inhibitory neurotransmitter in the brain, according to the scientists who published their study “Filamin A organizes γ‑aminobutyric acid type B receptors at the plasma membrane” in Nature Communications.
GABA plays a critical role in the brain, including controlling bodily movements and the transmission of pain. By activating specific receptors in the brain, GABA maintains proper brain activity by slowing down electric impulses as they travel between brain cells. The discovery that the protein filamin A is involved in positioning these receptors to the right place could enable researchers to develop new therapies to manage a range of neurological disorders, including multiple sclerosis.
“The γ-aminobutyric acid type B (GABAB) receptor is a prototypical family C G protein-coupled receptor (GPCR) that plays a key role in the regulation of synaptic transmission. Although growing evidence suggests that GPCR signaling in neurons might be highly organized in time and space, limited information is available about the mechanisms controlling the nanoscale organization of GABAB receptors and other GPCRs on the neuronal plasma membrane,” the investigators wrote.
“Using a combination of biochemical assays in vitro, single-particle tracking, and super-resolution microscopy, we provide evidence that the spatial organization and diffusion of GABAB receptors on the plasma membrane are governed by dynamic interactions with filamin A, which tethers the receptors to sub-cortical actin filaments.
“We further show that GABAB receptors are located together with filamin A in small nanodomains in hippocampal neurons. These interactions are mediated by the first intracellular loop of the GABAB1 subunit and modulate the kinetics of Gαi protein activation in response to GABA stimulation.”
“Filamin A answers a question that scientists have been asking about how GABA is able to control a range of functions in the brain. By acting like an anchor that precisely positions GABAB receptors where they are needed, it allows GABA to modulate a host of brain functions that are implicated in multiple neurological diseases,” said Davide Calebiro, MD, PhD, professor of molecular endocrinology at the University of Birmingham and lead author of the paper.
“While the GABA-A receptor gets most of the attention as it mediates rapid GABA responses, twin brother B which mediates slower responses is a huge potential drug target, and our findings could have significant impacts in treating everything from multiple sclerosis to epilepsy.
“Moreover, we hypothesize that defects in Filamin A could impair the normal localization of GABAB receptors in neurons, disrupting the correct processing of signals in the brain and ultimately leading to the brain not being able to communicate effectively with the rest of the body.”
Filamin A’s role in GABA activity was found due to research methods developed at the Centre of Membrane Proteins and Receptors (COMPARE), a research institute of the University of Birmingham in partnership with the University of Nottingham, according to Calebiro. In particular, the use of single molecule and super resolution microscopy approaches used by his lab have enabled the research team to directly follow individual receptors and filamin molecules as they interact on the surface of living cells with unprecedented detail.
