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J. Biol. Chem., Vol. 277, Issue 8, 6382-6390, February 22, 2002

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Altered Extracellular Signal-regulated Kinase Signal Transduction by the Muscarinic Acetylcholine and Metabotropic Glutamate Receptors after Cerebral Ischemia^*

Norio Takagi, Keiko Miyake-Takagi, Kaori Takagi, Hiroshi Tamura^§, and Satoshi Takeo

From the Faculty of Pharmaceutical Sciences, Department of Pharmacology and the ^§ Department of Clinical Biochemistry, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

To determine whether muscarinic acetylcholine receptors (mAChR) in the post-ischemic hippocampus may be involved in altered extracellular signal-regulated kinases (ERK) signal transduction, we have investigated changes in the activity of ERK1/2 induced by a muscarinic agonist, carbachol. Cerebral ischemia was produced in the rat by injecting 900 microspheres (48 µm in diameter) into the right internal carotid artery. Applying carbachol to the contralateral hippocampal slices from ischemic rats increased the phosphorylation of ERK1/2 but did not increase phosphorylation in the ipsilateral hippocampus. Analysis of M₁ mAChR binding showed that there was no significant difference in the number and K_d values between the hippocampi from naïve and ischemic rats. Immunoblotting analysis showed no significant difference in the amount of M₁ mAChR in both hemispheres. In contrast to carbachol stimulation, the protein kinase C activator induced an activation of ERK1/2 in the ipsilateral hippocampus. This increase was shown to occur in neurons by immunofluorescence colocalization study. Carbachol-stimulated tyrosine phosphorylation of the G_q/11, inositol 1,4,5-trisphosphate formation, and association of G_q/11 with phospholipase C1 were attenuated in the ipsilateral hippocampus. We also found that stimulation of group I metabotropic glutamate receptors, which are linked to G_q/11, failed to increase in phosphorylation of ERK1/2 in the ipsilateral hippocampus. These results suggest that failure in receptor-mediated tyrosine phosphorylation of the G_q/11 subunit and a defect in receptor-G_q/11-effector coupling in the ischemic hippocampus may be involved in alterations of ERK signal transduction.

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