Evidence that GABA ρ subunits contribute to functional ionotropic GABA receptors in mouse cerebellar Purkinje cells
- 8 November 2006
- journal article
- Published by Wiley in The Journal of Physiology
- Vol. 577 (1), 127-139
- https://doi.org/10.1113/jphysiol.2006.112482
Abstract
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 GABAC over other GABA receptors. Exogenous application of the GABAC-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 GABAC 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 GABAA receptors. Thus, we describe a population of ionotropic GABA receptors with a mixed GABAA/GABAC 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 GABAA α1 subunits in PCs. Finally, co-immunoprecipitation studies suggest that ρ subunits can form complexes with GABAA 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.Keywords
This publication has 44 references indexed in Scilit:
- Subtype-Specific GABA Transporter Antagonists Synergistically Modulate Phasic and Tonic GABAAConductances in Rat NeocortexJournal of Neurophysiology, 2005
- Interactions between ρ and γ2 subunits of the GABA receptorJournal of Neurochemistry, 2005
- Variations on an inhibitory theme: phasic and tonic activation of GABAA receptorsNature Reviews Neuroscience, 2005
- Functional characterization of rat ρ2 subunits expressed in HEK 293 cellsEuropean Journal of Neuroscience, 2005
- Evidence for Inhibition Mediated by Coassembly of GABAAand GABACReceptor Subunits in Native Central NeuronsJournal of Neuroscience, 2004
- Mechanism of GABAB receptor-mediated inhibition of spontaneous GABA release onto cerebellar Purkinje cellsEuropean Journal of Neuroscience, 2004
- Tonically active GABAA receptors: modulating gain and maintaining the toneTrends in Neurosciences, 2004
- Expression and dendritic mRNA localization of GABACreceptor ρ1 and ρ2 subunits in developing rat brain and spinal cordEuropean Journal of Neuroscience, 2002
- Response kinetics and pharmacological properties of heteromeric receptors formed by coassembly of GABA rho- and gamma2-subunitsProceedings Of The Royal Society B-Biological Sciences, 1999
- GABAC receptors: relatively simple transmitter-gated ion channels?Trends in Pharmacological Sciences, 1996