Subcellular compartment-specific molecular diversity of pre- and post-synaptic GABAB-activated GIRK channels in Purkinje cells

Laura Fernández-Alacid, Carolina Aguado, Francisco Ciruela, Ricardo Martín, José Colón, María José Cabañero, Martin Gassmann, Masahiko Watanabe, Ryuichi Shigemoto, Kevin Wickman, Bernhard Bettler, José Sánchez-Prieto, Rafael Luján

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Activation of G protein-gated inwardly-rectifying K+ (GIRK or Kir3) channels by metabotropic gamma-aminobutyric acid (B) (GABAB) receptors is an essential signalling pathway controlling neuronal excitability and synaptic transmission in the brain. To investigate the relationship between GIRK channel subunits and GABAB 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 GABAB 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 GABAB 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 GABAB 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 GABAB 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.

Original languageEnglish (US)
Pages (from-to)1363-1376
Number of pages14
JournalJournal of Neurochemistry
Volume110
Issue number4
DOIs
StatePublished - Aug 2009

Keywords

  • Cerebellum
  • Electron microscopy
  • Glutamate release
  • Immunohistochemistry
  • Potassium channels
  • Subunit composition

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