Receptor‐specific inhibition of GABA B ‐activated K + currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus

It has been shown that the activation of G q ‐coupled receptors (G q PCRs) in cardiac myocytes inhibits the G protein‐gated inwardly rectifying K + current ( I GIRK ) via receptor‐specific depletion of phosphatidylinositol 4,5‐bisphosphate (PIP 2 ). In this study, we investigated the mechanism of the receptor‐mediated regulation of I GIRK 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). I GIRK was activated by the GABA B receptor agonist, baclofen. When baclofen was repetitively applied at intervals of 2–3 min, the amplitude of the second I GIRK was 92.3 ± 1.7% of the first I GIRK 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 I GIRK to 54.8 ± 1.3% and 51.4 ± 0.6%, respectively. In PLCβ1 knockout mice, the effect of CCh on I GIRK was significantly reduced, whereas the effect of DHPG remained unchanged. The CCh‐mediated inhibition of I GIRK was almost completely abolished by PKC inhibitors and pipette solutions containing BAPTA. The DHPG‐mediated inhibition of I GIRK was attenuated by the inhibition of phospholipase A 2 (PLA 2 ), or the sequestration of arachidonic acid. We confirmed that DHPG eliminated the inhibition of I GIRK by arachidonic acid. These results indicate that muscarinic inhibition of I GIRK is mediated by the PLC/PKC signalling pathway, while group I mGluR inhibition of I GIRK occurs via the PLA 2 ‐dependent production of arachidonic acid. These results present a novel receptor‐specific mechanism for crosstalk between G q PCRs and GABA B receptors.