Phosphoinositide hydrolysis, Gαq, phospholipase C, and protein kinase C in post mortem human brain

Effects of post mortem interval, subject age, and alzheimer's disease

A. F. Greenwood, R. E. Powers, Richard S Jope

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Influences of post mortem time interval, subject age and Alzheimer's disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Gαq, β, δ and γ subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Gαq and the α and ζ protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Gαq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimer's disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Gαq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50%, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimer's disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimer's disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.

Original languageEnglish
Pages (from-to)125-138
Number of pages14
JournalNeuroscience
Volume69
Issue number1
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Type C Phospholipases
Phosphatidylinositols
Protein Kinase C
Alzheimer Disease
Hydrolysis
Brain
GTP-Binding Proteins
Second Messenger Systems
Guanosine Triphosphate
Protein Isoforms
Gq-G11 GTP-Binding Protein alpha Subunits
Carbachol
Cholinergic Receptors
Prefrontal Cortex
Cognition
Cholinergic Agents
Signal Transduction
Membranes
Pharmaceutical Preparations

Keywords

  • ACPD
  • AD
  • aging
  • Alzheimer's disease
  • cholinergic
  • EGTA
  • ethylene glycol bis (amino ethyl ether) tetra-acetate
  • G-protein
  • inositol
  • phosphatidylinositol
  • PI
  • SDS
  • sodium dodecyl sulfate
  • trans-1-aminocyclopentyl-1,3-dicarboxylic acid

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

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title = "Phosphoinositide hydrolysis, Gαq, phospholipase C, and protein kinase C in post mortem human brain: Effects of post mortem interval, subject age, and alzheimer's disease",
abstract = "Influences of post mortem time interval, subject age and Alzheimer's disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Gαq, β, δ and γ subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Gαq and the α and ζ protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Gαq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimer's disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Gαq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50{\%}, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimer's disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimer's disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.",
keywords = "ACPD, AD, aging, Alzheimer's disease, cholinergic, EGTA, ethylene glycol bis (amino ethyl ether) tetra-acetate, G-protein, inositol, phosphatidylinositol, PI, SDS, sodium dodecyl sulfate, trans-1-aminocyclopentyl-1,3-dicarboxylic acid",
author = "Greenwood, {A. F.} and Powers, {R. E.} and Jope, {Richard S}",
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pages = "125--138",
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TY - JOUR

T1 - Phosphoinositide hydrolysis, Gαq, phospholipase C, and protein kinase C in post mortem human brain

T2 - Effects of post mortem interval, subject age, and alzheimer's disease

AU - Greenwood, A. F.

AU - Powers, R. E.

AU - Jope, Richard S

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Influences of post mortem time interval, subject age and Alzheimer's disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Gαq, β, δ and γ subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Gαq and the α and ζ protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Gαq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimer's disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Gαq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50%, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimer's disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimer's disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.

AB - Influences of post mortem time interval, subject age and Alzheimer's disease were investigated on several components of the phosphoinositide second messenger system, including stimulation of [3H]phosphatidylinositol hydrolysis by GTP[S] and several receptor agonists and the levels of Gαq, β, δ and γ subtypes of phospholipase C, and five protein kinase C isoforms, in membranes prepared from post mortem human prefrontal cortex. Most of these components were stable with post mortem delays in the range of 5-21 h, but decreases of Gαq and the α and ζ protein kinase C subtypes were detected. Within the subject age range of 19-100 years, G-protein- and agonist-induced [3H]phosphatidylinositol hydrolysis decreased, as did levels of Gαq, but the levels of phospholipase C and protein kinase C subtypes were generally unchanged. In Alzheimer's disease, compared with age- and post mortem interval-matched controls, there was a decrease in [3H]phosphatidylinositol hydrolysis stimulated by G-proteins and by several receptor agonists, but the levels of Gαq and most of the phospholipase C and protein kinase C isoforms were unaffected. The greatest deficits, which were >50%, occurred with GTP[S]- and carbachol-induced [3H]phosphatidylinositol hydrolysis, indicating that this G-protein function and the response to cholinergic stimulation are significantly impaired in Alzheimer's disease. In summary a comprehensive assessment of several components of the phosphoinositide second messenger system was made in post mortem human brain. Most elements were stable within the post mortem interval range of 5-21 h, lending validity to measurements using these tissues. Significant age-related reductions in several components were identified, indicating loss of responses with increasing age. Most importantly, severe reductions in responses to several stimuli were found in Alzheimer's disease brain, deficits in signal transduction which may contribute to impaired cognition and to the limited therapeutic responses to drugs, such as those used to activate cholinergic receptors coupled with the phosphoinositide system.

KW - ACPD

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KW - G-protein

KW - inositol

KW - phosphatidylinositol

KW - PI

KW - SDS

KW - sodium dodecyl sulfate

KW - trans-1-aminocyclopentyl-1,3-dicarboxylic acid

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U2 - 10.1016/0306-4522(95)00220-D

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EP - 138

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

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ER -