Journal
JOURNAL OF NEUROCHEMISTRY
Volume 110, Issue 4, Pages 1363-1376Publisher
WILEY
DOI: 10.1111/j.1471-4159.2009.06229.x
Keywords
cerebellum; electron microscopy; glutamate release; immunohistochemistry; potassium channels; subunit composition
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Funding
- Spanish Ministry of Education and Science [BFU-2006-01896]
- CONSOLIDER [CSD2008-00005]
- Spanish 'Ministerio de Educacion y Ciencia' [BFU2007-64154/BFI]
- Instituto de Salud Carlos III [RD06/0026]
- Comunidad de Madrid [S-BIO-0170/2006]
- Sociedad Espanola de Farmacologia and Laboratorios Almirall
- NIH [MH061933, DA011806]
- Swiss Science Foundation [3100A0-117816]
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Activation of G protein-gated inwardly-rectifying K+ (GIRK or Kir3) channels by metabotropic gamma-aminobutyric acid (B) (GABA(B)) receptors is an essential signalling pathway controlling neuronal excitability and synaptic transmission in the brain. To investigate the relationship between GIRK channel subunits and GABA(B) receptors in cerebellar Purkinje cells at post- and pre-synaptic sites, we used biochemical, functional and immunohistochemical techniques. Co-immunoprecipitation analysis demonstrated that GIRK subunits are co-assembled with GABA(B) receptors in the cerebellum. Immunoelectron microscopy showed that the subunit composition of GIRK channels in Purkinje cell spines is compartment-dependent. Thus, at extrasynaptic sites GIRK channels are formed by GIRK1/GIRK2/GIRK3, post-synaptic densities contain GIRK2/GIRK3 and dendritic shafts contain GIRK1/GIRK3. The post-synaptic association of GIRK subunits with GABA(B) receptors in Purkinje cells is supported by the subcellular regulation of the ion channel and the receptor in mutant mice. At pre-synaptic sites, GIRK channels localized to parallel fibre terminals are formed by GIRK1/GIRK2/GIRK3 and co-localize with GABA(B) receptors. Consistent with this morphological evidence we demonstrate their functional interaction at axon terminals in the cerebellum by showing that GIRK channels play a role in the inhibition of glutamate release by GABA(B) receptors. The association of GIRK channels and GABA(B) receptors with excitatory synapses at both post- and pre-synaptic sites indicates their intimate involvement in the modulation of glutamatergic neurotransmission in the cerebellum.
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