GABAergic mIPSCs in rat cerebellar Purkinje cells are modulated by TrkB and mGluR1-mediated stimulation of Src.
Whilst protein tyrosine kinase (PTK) activity can modulate expressed GABAA receptors in cell culture, the physiological consequences on synaptic GABAA receptors are unknown. This was examined using whole-cell recording of bicuculline-sensitive mIPSCs in Purkinje cells (PCs) in cerebellar slices. Postsynaptic application of a peptide activator of the non-receptor PTK Src (Src-peptide) enhanced mIPSC amplitudes by 39 % in the presence of brain-derived neurotrophic factor (BDNF) only; neurotrophin-3 (NT-3) was ineffective in this regard. Thus Src and TrkB (the receptor for BDNF) can physiologically interact to modulate synaptic GABAA receptors. In the presence of BDNF, pharmacological activation of metabotrophic glutamate receptor subtype 1 (mGluR1) by (S)-3, 5-dihydrophenylglycine (3,5-DHPG) also lead to a 32 % enhancement of mIPSCs. This enhancement was blocked by intracellular dialysis of PCs with PP1, a selective inhibitor of Src. It is concluded that, whilst GABAA receptors are not constitutively regulated by endogenous PTK activity in PCs, co-activation of TrkB by BDNF and Src by mGluR1 is required to modulate GABAergic synapses in PCs.
Boxall
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AR
Arbeitsgruppe zellulare Neurobiologie (AG142), Max-Planck-Institut fur biophysikalische Chemie, Am Fassberg 11, D-37077 Gottingen, Germany. a.boxall@organon.nhe.akzonobel.nl
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000378:metabolism*; D009924:Organ Culture Techniques; D010636:Phenols / Q000494:pharmacology; D011689:Purkinje Cells / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D020813:Receptor, trkB / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012118:Resorcinols / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013569:Synapses / Q000737:chemistry / Q000201:enzymology; D014638:Vanadates / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D009842:Oligopeptides; D010636:Phenols; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C040475:Src peptide; C104077:metabotropic glutamate receptor type 1; D014638:Vanadates; C062898:lavendustin A; D005680:gamma-Aminobutyric Acid; C079215:3,5-dihydroxyphenylglycine; D020813:Receptor, trkB; D019311:Staurosporine; D005998:Glycine; D001640:Bicuculline