Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics

GABA_B receptors, the most abundant inhibitory G-protein coupled receptors in the mammalian brain, display pronounced diversity in functional properties, cellular signaling and subcellular distribution. Here we use high-resolution functional proteomics to identify the building blocks of these receptors in the rodent brain. The analyses demonstrated that native GABA_B receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: The receptor core is assembled from GABA_B1a/b, GABA_B2, four KCTD proteins and a distinct set of G-protein subunits, while the receptors’ periphery is mostly formed by transmembrane proteins of different classes. In particular, the periphery-forming constituents include signaling effectors such as Cav2 and HCN channels, and the proteins AJAP1 and amyloid-bA4 both of which tightly associate with the sushi-domains of GABA_B1a. The results unravel the molecular diversity of GABA_B receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.