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. Access through your institution Buy or subscribe This is a preview of

subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 51 print issues and online access $199.00 per year only

$3.90 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout

ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS PHOSPHATIDYLINOSITOL

4,5-BISPHOSPHATE (PIP2) FACILITATES NOREPINEPHRINE TRANSPORTER DIMERIZATION AND MODULATES SUBSTRATE EFFLUX Article Open access 17 November 2022 A NEURODEVELOPMENTAL DISORDER MUTATION LOCKS G

PROTEINS IN THE TRANSITORY PRE-ACTIVATED STATE Article Open access 05 August 2024 AN INTERACTION BETWEEN PRRT2 AND NA+/K+ ATPASE CONTRIBUTES TO THE CONTROL OF NEURONAL EXCITABILITY Article

Open access 17 March 2021 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). Article  CAS  Google Scholar  * Rhee, S. G. & Bae, Y. S. Regulation of phosphoinositide specific phospholipase C isozymes. _J. Biol. Chem._ 272, 15045–15048 (1997). Article

  CAS  Google Scholar  * 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). Article  ADS  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article  ADS  CAS  Google Scholar  * Tecott, L. H._et al_. Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors.

_Nature_ 374, 542–546 (1995). Article  ADS  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * Sloviter, R. S. Decreased hippocampal inhibition and a selective loss of interneurons in

experimental epilepsy. _Science_ 235, 73–76 (1987). Article  ADS  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * Buckley, N. J., Bonner, T. I. & Brann, M. R. Localization of muscarinic

receptor mRNAs in rat brain. _J. Neurosci._ 8, 4646–4652 (1988). Article  CAS  Google Scholar  * 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). Article

  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * Pitler, T. A. & Alger, B. E. Cholinergic excitation of GABAergic interneurons in the rat hippocampal slice. _J.

Physiol. (Lond.)_ 450, 127–142 (1992). Article  CAS  Google Scholar  * Bartus, R. T., Dean, R. I. II, Beer, B. & Lippa, A. S. The cholinergic hypothesis of geriatric memory dysfunction.

_Science_ 217, 408–414 (1982). Article  ADS  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article  ADS  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * Masu, M., Tanabe, Y.,

Tsuchida, K., Shigemoto, R. & Nakanishi, S. Sequence and expression of a metabotropic glutamate receptor. _Nature_ 349, 760–765 (1991). Article  ADS  CAS  Google Scholar  * Aiba, A. _et

al_. Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice. _Cell_ 79, 377–388 (1994). Article  CAS  Google Scholar  * 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). Article  ADS  CAS 

Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article  Google Scholar  * 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). Article  CAS  Google Scholar  * 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). Article  CAS  Google Scholar  * Schoepp, D. D., Johnson, B. G., True, R. A. & Monn,

J. A. Comparison of (1_S_,3_R_)-1-aminocyclopentane-1,3-dicarboxylic acid (1_S_,3_R_-ACPD) and 1_R_,3_S_-ACPD-stimulated brain phosphoinositide hydrolysis. _Eur. J. Pharmacol._ 207, 351–353

(1991). Article  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION Author notes * Daesoo Kim, Ki Sun Jun and Young-Hoon Kim: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS *

Department of Life Science, Pohang University of Science and Technology, San-31, Hyoja-Dong, 790-784, Pohang, Republic of Korea Seong Beom Lee, Nae-Gyu Kang, Do Sik Min, Sung Ho Ryu, 

Pann-Ghill Suh & Hee-Sup Shin * Institute of Neuroscience, Inje University, 633-165, Gaegum-Dong, 614-735, Pusan, Republic of Korea Young-Hoon Kim Authors * Daesoo Kim View author

publications You can also search for this author inPubMed Google Scholar * Ki Sun Jun View author publications You can also search for this author inPubMed Google Scholar * Seong Beom Lee

View author publications You can also search for this author inPubMed Google Scholar * Nae-Gyu Kang View author publications You can also search for this author inPubMed Google Scholar * Do

Sik Min View author publications You can also search for this author inPubMed Google Scholar * Young-Hoon Kim View author publications You can also search for this author inPubMed Google

Scholar * Sung Ho Ryu View author publications You can also search for this author inPubMed Google Scholar * Pann-Ghill Suh View author publications You can also search for this author

inPubMed Google Scholar * Hee-Sup Shin View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Hee-Sup Shin. RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 18 July 1997 * Accepted: 05 August 1997 * Issue Date: 18 September 1997 * DOI:

https://doi.org/10.1038/38508 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently

available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative