Abstract
A variety of extracellular signals are transduced across the cell membrane by the enzyme phosphoinositide-specific phospholipase C-beta (PLC-beta) coupled with guanine-nucleotide-binding G proteins. There are four isoenzymes of PLC-beta, beta1-beta4, but their functions in vivo are not known. Here we investigate the role of PLC-beta1 and PLC-beta4 in the brain by generating null mutations in mice: we found that PLCbeta1-/- mice developed epilepsy and PLCbeta4-/- mice showed ataxia. We determined the molecular basis of these phenotypes and show that PLC-beta1 is involved in signal transduction in the cerebral cortex and hippocampus by coupling predominantly to the muscarinic acetylcholine receptor, whereas PLC-beta4 works through the metabotropic glutamate receptor in the cerebellum, illustrating how PLC-beta isoenzymes are used to generate different functions in the brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia / enzymology
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Ataxia / genetics
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Ataxia / metabolism
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Binding Sites
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Brain / enzymology
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Brain / metabolism*
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Carbachol / pharmacology
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Cerebellum / abnormalities
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Cycloleucine / analogs & derivatives
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Cycloleucine / pharmacology
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Epilepsy / enzymology
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Epilepsy / genetics
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Epilepsy / metabolism
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Hippocampus / enzymology
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Hippocampus / metabolism
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Hippocampus / pathology
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Mice
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Mice, Knockout
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Muscarinic Agonists / pharmacology
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Mutagenesis
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Phosphatidylinositols / metabolism
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Phospholipase C beta
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Piperazines / pharmacology
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Receptors, Metabotropic Glutamate / antagonists & inhibitors
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Receptors, Metabotropic Glutamate / metabolism*
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Receptors, Muscarinic / metabolism*
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Serotonin Receptor Agonists / pharmacology
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Signal Transduction
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Type C Phospholipases / genetics
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Type C Phospholipases / metabolism*
Substances
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Isoenzymes
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Muscarinic Agonists
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Phosphatidylinositols
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Piperazines
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Receptors, Metabotropic Glutamate
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Receptors, Muscarinic
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Serotonin Receptor Agonists
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Cycloleucine
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1-amino-1,3-dicarboxycyclopentane
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Carbachol
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Type C Phospholipases
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Phospholipase C beta
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Plcb1 protein, mouse
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Plcb4 protein, mouse
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1-(3-chlorophenyl)piperazine