GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.

• Keywords
• GABAB receptor, auditory, hearing loss, neuronal excitability, synaptic transmission, tinnitus,
• MeSH
• Cell Membrane MeSH
• gamma-Aminobutyric Acid MeSH
• Deafness * MeSH
• Cognition MeSH
• Receptors, GABA-B * MeSH
• Mammals MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• gamma-Aminobutyric Acid MeSH
• Receptors, GABA-B * MeSH

GABAB receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aβ, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aβ formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aβ formation.

• MeSH
• Amyloid metabolism   MeSH
• Amyloid beta-Peptides chemistry   metabolism   MeSH
• Axonal Transport * MeSH
• Axons metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Dendrites metabolism   MeSH
• Epitopes metabolism   MeSH
• HEK293 Cells MeSH
• Kinesins metabolism   MeSH
• Humans MeSH
• Cell Adhesion Molecules chemistry   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Nerve Tissue Proteins chemistry   metabolism   MeSH
• GTP-Binding Proteins metabolism   MeSH
• Proteomics MeSH
• Receptors, GABA-B metabolism   MeSH
• Amino Acid Sequence MeSH
• Signal Transduction MeSH
• Protein Stability MeSH
• Synapses metabolism   MeSH
• Protein Binding MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Amyloid MeSH
• Amyloid beta-Peptides MeSH
• Epitopes MeSH
• Kinesins MeSH
• Cell Adhesion Molecules MeSH
• Nerve Tissue Proteins MeSH
• GTP-Binding Proteins MeSH
• Receptors, GABA-B MeSH

UNLABELLED: GABAB receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, GABA. GABAB receptors were shown to associate with homo-oligomers of auxiliary KCTD8, KCTD12, KCTD12b, and KCTD16 subunits (named after their T1 K+-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABAB receptors also associate with hetero-oligomers of KCTD subunits. Coimmunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero-oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer measurements in live cells reveal that KCTD12/KCTD16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties on G-protein-activated Kir3 currents. During prolonged receptor activation (one min) KCTD12/KCTD16 hetero-oligomers produce moderately desensitizing fast deactivating K+ currents, whereas KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and nondesensitizing slowly deactivating currents, respectively. During short activation (2 s) KCTD12/KCTD16 hetero-oligomers produce nondesensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/KCTD16 hetero-oligomers increase the duration of slow IPSCs. In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABAB receptors and modulates physiologically induced K+ current responses in the hippocampus. SIGNIFICANCE STATEMENT: The KCTD proteins 8, 12, and 16 are auxiliary subunits of GABAB receptors that differentially regulate G-protein signaling of the receptor. The KCTD proteins are generally assumed to function as homo-oligomers. Here we show that the KCTD proteins also assemble hetero-oligomers in all possible dual combinations. Experiments in live cells demonstrate that KCTD hetero-oligomers form at least tetramers and that these tetramers directly interact with the receptor and the G-protein. KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties to GABAB receptor-induced Kir3 currents in heterologous cells. KCTD12/KCTD16 hetero-oligomers are abundant in the hippocampus, where they prolong the duration of slow IPSCs in pyramidal cells. Our data therefore support that KCTD hetero-oligomers modulate physiologically induced K+ current responses in the brain.

• Keywords
• G-protein coupled receptor, GABA-B, GPCR, KCTD12, KCTD16, Kir3,
• MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Potassium Channels genetics   metabolism   MeSH
• Electrophysiological Phenomena genetics   MeSH
• Excitatory Postsynaptic Potentials genetics   MeSH
• Kinetics MeSH
• Cricetinae MeSH
• Patch-Clamp Techniques MeSH
• Brain Chemistry genetics   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Receptors, GABA-B genetics   metabolism   MeSH
• Receptors, KIR metabolism   MeSH
• Receptors, G-Protein-Coupled metabolism   MeSH
• Animals MeSH
• Check Tag
• Cricetinae MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Potassium Channels MeSH
• Receptors, GABA-B MeSH
• Receptors, KIR MeSH
• Receptors, G-Protein-Coupled MeSH

GABAB receptors assemble from GABAB1 and GABAB2 subunits. GABAB2 additionally associates with auxiliary KCTD subunits (named after their K(+) channel tetramerization-domain). GABAB receptors couple to heterotrimeric G-proteins and activate inwardly-rectifying K(+) channels through the βγ subunits released from the G-protein. Receptor-activated K(+) currents desensitize in the sustained presence of agonist to avoid excessive effects on neuronal activity. Desensitization of K(+) currents integrates distinct mechanistic underpinnings. GABAB receptor activity reduces protein kinase-A activity, which reduces phosphorylation of serine-892 in GABAB2 and promotes receptor degradation. This form of desensitization operates on the time scale of several minutes to hours. A faster form of desensitization is induced by the auxiliary subunit KCTD12, which interferes with channel activation by binding to the G-protein βγ subunits. Here we show that the two mechanisms of desensitization influence each other. Serine-892 phosphorylation in heterologous cells rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. Likewise, protein kinase-A activation in hippocampal neurons slows fast desensitization of GABAB receptor-activated K(+) currents while protein kinase-A inhibition accelerates fast desensitization. Protein kinase-A fails to regulate fast desensitization in KCTD12 knock-out mice or knock-in mice with a serine-892 to alanine mutation, thus demonstrating that serine-892 phosphorylation regulates KCTD12-induced desensitization in vivo. Fast current desensitization is accelerated in hippocampal neurons carrying the serine-892 to alanine mutation, showing that tonic serine-892 phosphorylation normally limits KCTD12-induced desensitization. Tonic serine-892 phosphorylation is in turn promoted by assembly of receptors with KCTD12. This cross-regulation of serine-892 phosphorylation and KCTD12 activity sharpens the response during repeated receptor activation.

• Keywords
• G-protein coupled receptor, GABA-B, GPCR, Kir3, PKA,
• MeSH
• Alanine genetics   metabolism   MeSH
• CHO Cells MeSH
• Cricetulus MeSH
• Potassium metabolism   MeSH
• Phosphorylation MeSH
• Hippocampus cytology   metabolism   MeSH
• Cells, Cultured MeSH
• Patch-Clamp Techniques MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Neurons metabolism   MeSH
• Cyclic AMP-Dependent Protein Kinases metabolism   MeSH
• GTP-Binding Proteins metabolism   MeSH
• Receptors, GABA-B genetics   metabolism   MeSH
• Receptors, GABA genetics   metabolism   MeSH
• Serine genetics   metabolism   MeSH
• Amino Acid Substitution MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alanine MeSH
• Potassium MeSH
• pfetin protein, mouse MeSH Browser
• Cyclic AMP-Dependent Protein Kinases MeSH
• GTP-Binding Proteins MeSH
• Receptors, GABA-B MeSH
• Receptors, GABA MeSH
• Serine MeSH