Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus

Authors


Corresponding author W-K. Ho: Department of Physiology, Seoul National University College of Medicine, 28 Yonkeun-Dong, Jongno-gu, Seoul 110-799, Korea.  Email: wonkyung@snu.ac.kr

Abstract

It has been shown that the activation of Gq-coupled receptors (GqPCRs) in cardiac myocytes inhibits the G protein-gated inwardly rectifying K+ current (IGIRK) via receptor-specific depletion of phosphatidylinositol 4,5-bisphosphate (PIP2). In this study, we investigated the mechanism of the receptor-mediated regulation of IGIRK in acutely isolated hippocampal CA1 neurons by the muscarinic receptor agonist, carbachol (CCh), and the group I metabotropic glutamate receptor (mGluR) agonist, 3,5-dihydroxyphenylglycine (DHPG). IGIRK was activated by the GABAB receptor agonist, baclofen. When baclofen was repetitively applied at intervals of 2–3 min, the amplitude of the second IGIRK was 92.3 ± 1.7% of the first IGIRK in control. Pretreatment of neurons with CCh or DHPG prior to the second application of baclofen caused a reduction in the amplitude of the second IGIRK to 54.8 ± 1.3% and 51.4 ± 0.6%, respectively. In PLCβ1 knockout mice, the effect of CCh on IGIRK was significantly reduced, whereas the effect of DHPG remained unchanged. The CCh-mediated inhibition of IGIRK was almost completely abolished by PKC inhibitors and pipette solutions containing BAPTA. The DHPG-mediated inhibition of IGIRK was attenuated by the inhibition of phospholipase A2 (PLA2), or the sequestration of arachidonic acid. We confirmed that DHPG eliminated the inhibition of IGIRK by arachidonic acid. These results indicate that muscarinic inhibition of IGIRK is mediated by the PLC/PKC signalling pathway, while group I mGluR inhibition of IGIRK occurs via the PLA2-dependent production of arachidonic acid. These results present a novel receptor-specific mechanism for crosstalk between GqPCRs and GABAB receptors.

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