Synaptotagmin-11 facilitates transport and stabilization of pre-assembled presynaptic GABAB receptor/Cav2.2 signaling complexes

GABAB receptors (GBRs), the G protein-coupled receptors for GABA, regulate synaptic transmission throughout the brain. A main synaptic GBR function is the gating of ion channels. However, where stable GBR-effector channel signaling units are formed in the biosynthetic pathway has remained unclear. Here we show that the vesicular protein synaptotagmin-11 (Syt11) binds the auxiliary GBR subunit KCTD16 and Cav2.2 channels. This enables Syt11 to recruit GBR/Cav2.2 channel complexes to post-Golgi vesicles that transport the pre-assembled signaling complexes in axons and dendrites. Bimolecular fluorescence complementation experiments reveal that GBR/Syt11 complexes are delivered to synaptic sites. Furthermore, Syt11 stabilizes GBRs and Cav2.2 channels at the neuronal plasma membrane by inhibiting constitutive internalization. Syt11-deficient neurons exhibit reduced glutamatergic synaptic transmission and impaired GBR-mediated presynaptic inhibition, thus highlighting a key role for Syt11 in the transport and stable expression of functional GBR/Cav2.2 complexes at synapses.