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Evidence that GABA ρ subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells
Author(s) -
Harvey Victoria L.,
Duguid Ian C.,
Krasel Cornelius,
Stephens Gary J.
Publication year - 2006
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.112482
Subject(s) - ionotropic effect , gabaa receptor , inhibitory postsynaptic potential , bicuculline , chemistry , postsynaptic potential , agonist , neurotransmission , neuroscience , receptor , biology , glutamate receptor , biochemistry
Ionotropic γ‐amino butyric acid (GABA) receptors composed of heterogeneous molecular subunits are major mediators of inhibitory responses in the adult CNS. Here, we describe a novel ionotropic GABA receptor in mouse cerebellar Purkinje cells (PCs) using agents reported to have increased affinity for ρ subunit‐containing GABA C over other GABA receptors. Exogenous application of the GABA C ‐preferring agonist cis ‐4‐aminocrotonic acid (CACA) evoked whole‐cell currents in PCs, whilst equimolar concentrations of GABA evoked larger currents. CACA‐evoked currents had a greater sensitivity to the selective GABA C antagonist (1,2,5,6‐tetrahydropyridin‐4‐yl)methylphosphinic acid (TPMPA) than GABA‐evoked currents. Focal application of agonists produced a differential response profile; CACA‐evoked currents displayed a much more pronounced attenuation with increasing distance from the PC soma, displayed a slower time‐to‐peak and exhibited less desensitization than GABA‐evoked currents. However, CACA‐evoked currents were also completely blocked by bicuculline, a selective agent for GABA A receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABA A /GABA C pharmacology. TPMPA reduced inhibitory synaptic transmission at interneurone–Purkinje cell (IN–PC) synapses, causing clear reductions in miniature inhibitory postsynaptic current (mIPSC) amplitude and frequency. Combined application of NO‐711 (a selective GABA transporter subtype 1 (GAT‐1) antagonist) and SNAP‐5114 (a GAT‐(2)/3/4 antagonist) induced a tonic GABA conductance in PCs; however, TPMPA had no effect on this current. Immunohistochemical studies suggest that ρ subunits are expressed predominantly in PC soma and proximal dendritic compartments with a lower level of expression in more distal dendrites; this selective immunoreactivity contrasted with a more uniform distribution of GABA A α1 subunits in PCs. Finally, co‐immunoprecipitation studies suggest that ρ subunits can form complexes with GABA A receptor α1 subunits in the cerebellar cortex. Overall, these data suggest that ρ subunits contribute to functional ionotropic receptors that mediate a component of phasic inhibitory GABAergic transmission at IN–PC synapses in the cerebellum.