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Signal transduction in the brain: modulation of receptor-mediated inositol phospholipid breakdown by potassium and fluoride ions
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
1990 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neurotransmitter receptor types mediating the generation of intracellular signals are of two types; ligand-gated ion channels and G protein coupled receptors. The effector enzyme phosphoinositide-specific phospholipase C (PLC) is modulated by stimulation of G protein coupled receptors, leading to an increased breakdown of inositol phospholipids ("Ptdlns breakdown").In recent years, the receptors in the brain coupled to PLC and modulation of such receptor-mediated Ptdlns breakdown have been characterised. One such modulation is the "potassium effect", whereby an increase in the assay [K+] from 6 to 18 mM potentiates the Ptdlns breakdown response to the muscarinic agonist carbachol in the rat brain. It has been speculated that this effect is one way of enhancing the signal :noise ratio of muscarinic neurotransmission. The mechanisms responsible for the potassium effect have been studied in this thesis.Initial methodological studies indicated that the temperature of the Krebs buffer used after tissue dissection was an important factor regulating the Ptdlns response to receptor stimulation. Expressing the Ptdlns breakdown response as a fraction of the total labelled phosphoinositides was more useful than other ways of expressing the data. Acid extraction of the Lipid fraction was also superior to neutral extraction.Miniprismspreparedfrompig striatum and hippocampus showed qualitative (but not quantitative) similarities with the rat with respect to stimulation by carbachol, noradrenaline and the potassium effect. Dopamine also stimulated Ptdlns breakdown, though probably via a noradrenergic mechanism.The enhancing actions of potassium appeared to be selective for muscarinic Ml-type receptors. Thus glutamate, quisqualate and NaF-stimulated Ptdlns breakdown are not affected by raised [K+].The potassium effect is brought about by two mechanisms. In calcium-free Krebs buffer, the effect could be mimicked by the calcium channel agonist BAY K-8644 and partially antagonised by verapamil. At an assay [Ca2*] of 2.52 mM, however, modulation of calcium uptake had little effect on carbachol-stimulated Ptdlns breakdown at either normal or raised [K+]. The synergy between potassium and carbachol at252 mM Ca?+ is not dependent upon tissue depolarisation perse, since other ways of depolarising the tissue did not enhance the response to carbachol. It is suggested that potassium might have a direct effect on the muscarinic Ml-type receptor - G protein - PLC complex.In order to investigate this possibility, the effect of fluoride ions (which activate G proteins via formation of AlF4) on basal and carbachol-stimulated Ptdlns breakdown was investigated. Fluoride ions inhibited the enhanced breakdown response to carbachol found at raised [K+]. However, this effect is secondary to effects of fluoride on PLC substrate availibility rather than on G protein function.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 1990. , 52 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 274
Keyword [en]
Inositol phospholipid breakdown, muscarinic receptors, potassium, fluoride, rat brain, pig brain
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:umu:diva-68968ISBN: 91-7174-504-1OAI: diva2:619258
Public defence
1990-06-15, Föreläsninssal A5, Byggnad 6A, Regionsjukhuset, Umeå universitet, Umeå, 09:15
Available from: 2013-05-02 Created: 2013-05-02 Last updated: 2013-05-02Bibliographically approved

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