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Phospholipase C isozymes selectively couple to specific neurotransmitter receptors

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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Figure 1: The PH, X and Y domains are indicated on the protein, where PH is a pleckstrin-homology domain and X and Y are catalytic domains.
Figure 2: Epileptic seizures in PLCβ1−/− mice.
Figure 3: Immunohistochemical analysis of hippocampus in a wild type (a, c, d) and a PLCβ1/− littermate that experienced seizures (b, e, f) with somatostatin polyclonal antibody (Zymed).
Figure 4: LiCl-amplified agonist-induced phosphoinositide (PI) hydrolysis in a, PLCβ1−/−, and b, PLCβ4−/− brain slices. Agonist-induced PI hydrolysis was assayed as described in Methods.

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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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Correspondence to Hee-Sup Shin.

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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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