Filamin A organizes γ-aminobutyric acid type B receptors at the plasma membrane

GABA(B) receptors mediate the effects of the main inhibitory neurotransmitter in the brain. Here, authors identify the cytoskeletal protein filamin A as a key player that controls the exact location and function of GABA(B) receptors at the cell surface. The gamma-aminobutyric acid type B (GABA(B)) 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 GABA(B) receptors and other GPCRs on the neuronal plasma membrane. 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 GABA(B) 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 GABA(B) receptors are located together with filamin A in small nanodomains in hippocampal neurons. These interactions are mediated by the first intracellular loop of the GABA(B1) subunit and modulate the kinetics of G alpha(i) protein activation in response to GABA stimulation.

Automated summary

GABA(B) receptors are precisely located and regulated by dynamic interactions with Filamin A, which is a cytoskeletal protein. This study provides evidence that the spatial organization and diffusion of GABA(B) receptors on the plasma membrane are governed by Filamin A, and these interactions modulate the kinetics of G alpha(i) protein activation in response to GABA stimulation.