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¹ National Research Laboratory for Cell Physiology and Department of Physiology, Seoul National University College of Medicine, Jongno-gu, Seoul 110–799, Korea

We showed in our previous study that in hippocampal CA1 neurons the stimulation of muscarinic receptors inhibited the GIRK current (I_GIRK) via a PLC/PKC pathway, whereas group I metabotropic glutamate receptors (mGluR) inhibited I_GIRK via a PLA₂/arachidonic acid pathway. In this study, we present evidence that receptor-mediated signalling pathways activated by the two G_q-coupled receptors (G_qPCRs) converge on the inhibition of GIRK channel–PIP₂ interaction. I_GIRK was activated in acutely isolated hippocampal CA1 neurons by repetitive application of baclofen, a GABA_B receptor agonist, with a 2–3 min interval. When both CCh and DHPG were pretreated before the second I_GIRK activation, the magnitude of the second I_GIRK was 52.2 ± 2.5% of the first I_GIRK, which was not significantly different from the magnitude of inhibition by CCh or DHPG alone. This result shows that the effects of muscarinic receptor and group I mGluR stimulation on I_GIRK are not additive but occlusive, suggesting that each pathway may converge to a common mechanism that finally regulates I_GIRK. To test the involvement of PIP₂ in this mechanism, the effect of CCh and DHPG on I_GIRK was tested in cells loaded with exogenous PIP₂. The inhibition of I_GIRK by CCh or DHPG was almost completely abolished in PIP₂-loaded cells. We confirmed that the inhibition of I_GIRK by direct application of phorbol ester or arachidonic acid was also completely reversed in PIP₂-loaded cells. These results indicate that the decrease in PIP₂–channel interactions is the final common mechanism responsible for G_qPCR-induced inhibitions of I_GIRK mediated by PKC and arachidonic acid.

(Received 23 May 2007; accepted after revision 19 June 2007; first published online 21 June 2007)
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{at}snu.ac.kr

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