Abstract
A variety of extracellular signals are transduced across the cell membrane by the enzyme phosphoinositide-specific phospholipase C-β (PLC-β) coupled with guanine-nucleotide-binding G proteins1. There are four isoenzymes of PLC-β, β1–β4, but their functions in vivo are not known. Here we investigate the role of PLC-β1 and PLC-β4 in the brain by generating null mutations in mice: we found that PLCβ1−/− mice developed epilepsy and PLCβ4−/− mice showed ataxia. We determined the molecular basis of these phenotypes and show that PLC-β1 is involved in signal transduction in the cerebral cortex and hippocampus by coupling predominantly to the muscarinic acetylcholine receptor, whereas PLC-β4 works through the metabotropic glutamate receptor in the cerebellum, illustrating how PLC-β isoenzymes are used to generate different functions in the brain.
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References
Fisher, S. K., Heackock, A. M. & Agaranoff, B. W. Inositol lipids and signal transduction in the nervous system: An update. J. Neurochem. 58, 18–38 (1992).
Rhee, S. G. & Bae, Y. S. Regulation of phosphoinositide specific phospholipase C isozymes. J. Biol. Chem. 272, 15045–15048 (1997).
Ross, C. A., MacCumber, M. W., Glatt, C. E. & Snyder, S. H. Brain phospholipase C isozymes: Differential mRNA localizations by in situ hybridization. Proc. Natl Acad. Sci. USA 86, 2923–2927 (1989).
Tanaka, O. & Kondo, H. Localization of mRNA for three novel members (β3, β4 and γ2) of phospholipase C family in mature rat brain. Neurosci. Lett. 182, 17–20 (1994).
Jiang, H.et al. Phospholipase C β4 is involved in modulating the visual response in mice. Proc. Natl Acad. Sci. USA 93, 14598–14601 (1996).
Tecott, L. H.et al. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374, 542–546 (1995).
Stafstrom, C. E., Thompson, J. L. & Holms, G. L. Kainic acid seizures in the developing brain: Status epilepticus and spontaneous recurrent seizures. Dev. Brain Res. 65, 227–236 (1992).
Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235, 73–76 (1987).
de Lanerolle, N. C., Kim, J. H., Robbins, R. J. & Spencer, D. D. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res. 495, 387–395 (1989).
Buckley, N. J., Bonner, T. I. & Brann, M. R. Localization of muscarinic receptor mRNAs in rat brain. J. Neurosci. 8, 4646–4652 (1988).
Biddlecome, G. H., Berstein, G. & Ross, E. M. Regulation of phospholipase C-β1 by Gq and m1 muscarinic cholinergic receptor. Steady-state balance of receptor-mediated activation and GTPase-activating protein-promoted deactivation. J. Biol. Chem. 271, 7999–8007 (1996).
Buzsaki, G., Ponomareff, G. L., Bayardo, F., Ruiz, R. & Gage, F. H. Neuronal activity in the subcortically denervated hippocampus: a chronic model for epilepsy. Neuroscience 28, 527–538 (1989).
Pitler, T. A. & Alger, B. E. Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. J. Physiol. (Lond.) 450, 127–142 (1992).
Bartus, R. T., Dean, R. I. II, Beer, B. & Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction. Science 217, 408–414 (1982).
Crews, F. T., Kurian, P. & Freund, G. Cholinergic and serotonergic stimulation of phophoinositide hydrolysis is decreased in Alzheimer disease. Life Sci. 55, 1993–2002 (1994).
Kelly, J. F. et al. Amyloid β-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons. Proc. Natl Acad. Sci. USA 93, 6753–6758 (1996).
Hesdorffer, D. C., Hauser, W. A., Annegers, J. F., Kokmen, E. & Rocca, W. A. Dementia and adult-onset unprovoked seizures. Neurology 46, 727–730 (1996).
Mendez, M. F., Catanzaro, P., Doss, R. C., Arguello, R. & Frey, W. H. Seizures in Alzheimer's disease: clinicopathologic study. J. Geriatr. Psychiatr. Neurol. 7, 230–233 (1994).
Masu, M., Tanabe, Y., Tsuchida, K., Shigemoto, R. & Nakanishi, S. Sequence and expression of a metabotropic glutamate receptor. Nature 349, 760–765 (1991).
Aiba, A. et al. Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. Cell 79, 377–388 (1994).
Dippel, E., Kalkbrenner, F., Wittig, B. & Schultz, G. Aheterotrimeric G protein complex couples the muscarinic m1 receptor to phospholipase C-β. Proc. Natl Acad. Sci. USA 93, 1391–1396 (1996).
Frankel, W. N., Johanson, C. M. & Lutz, C. M. Congenic strains reveal effects of the epilepsy quantitative trait locus, EL2, separate from other EL loci. Mamm. Genome 6, 839–843 (1995).
Kim, D. G., Kang, H. M., Jang, S. K. & Shin, H.-S. Construction of a bifunctional mRNA in the mouse by using the internal ribosomal entry site of the encephalomyocarditis virus. Mol. Cell. Biol. 13, 3636–3643 (1992).
Kim, M. J. et al. Cloning of cDNA encoding phospholipase C-β4, a new member of the phospholipase C. Biochem. Biophys. Res. Commun. 194, 706–712 (1993).
Berridge, M. J. et al. Change in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem. J. 212, 473–482 (1983).
Schoepp, D. D., Johnson, B. G., True, R. A. & Monn, J. A. Comparison of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and 1R,3S-ACPD-stimulated brain phosphoinositide hydrolysis. Eur. J. Pharmacol. 207, 351–353 (1991).
Acknowledgements
This Letter is dedicated to the late Dr. Hogil Kim, the former president of POSTECH, who made this work possible. H.-S.S. thanks E. Park for comments on the manuscript and E. B. Lee and B. J. Pak for their early contribution to this work. We thank S. G. Rhee for PLC-β1 cDNA, Y.Namkung for ES cell culture, I.S. Kim, I. B. Kim, H. D. Noh, C. T. Choi and I. S. Lee for help with histology, and H. Y. Lee for video processing. This work was supported in part by a genetic engineering grant from the Ministry of Education and a medical science grant from the Ministry of Health and Welfare of Korea, and by grants from the Basic Science Research Institute and from the School of Environmental Engineering, POSTECH.
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Kim, D., Jun, K., Lee, S. et al. Phospholipase C isozymes selectively couple to specific neurotransmitter receptors. Nature 389, 290–293 (1997). https://doi.org/10.1038/38508
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DOI: https://doi.org/10.1038/38508
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