Alterations of G‐protein Coupling Function in Phosphoinositide Signalling Pathways of Rat Hippocampus by Ischaemic Brain Injury

Abstract

The activation of membrane-associated phospholipase C is rapidly and transiently induced in the central nervous system by a variety of stimuli. Ischaemic brain injury is one of the situations that leads to a dramatic increase in polyphosphoinositide (PPI) turnover. In this study, stimulation of PPI hydrolysis by glutamate (500 microM) was measured in hippocampal slices from rats up to 21 days after an ischaemic insult of 30 min. Ischaemia was induced using the four-vessel occlusion method. PPI hydrolysis elicited by glutamate was significantly increased in the slices prepared from ischaemic rats 24 h after reperfusion, the accumulation of inositol phosphates (InsPs) and inositol 1,4,5-trisphosphate (Insp3) was 614 +/- 74% (n = 8) and 182 +/- 11% (n = 9) of the basal level respectively. This potentiation was also observed 21 days after ischaemia. Hyper-responsiveness to glutamate was also accompanied by an increase in AIF4(-)-stimulated formation of [3H]inositol phosphates. In addition, global ischaemia did not change either high-affinity [3H]glutamate binding in hippocampal membranes or the stimulation of PPI hydrolysis by carbachol or noradrenaline in hippocampal slices. The present results suggest that the increased responsiveness to glutamate is the result, at least in part, of functional changes at the G-protein level, and may contribute to the pathophysiology of ischaemic brain injury or to the regenerative phenomena that accompany ischaemic damage.

Advance of signal transduction pathways in normal cell

“…Under the catalysis of PLC, phosphatidylinositol biphosphate (PIP2) decomposes into inositol triphosphate (IP3) and diacylglycerol (DG), which afects two branches of this pathway respectively (Kim NH et al, 2011). The extracellular signals that stimulate the metabolism of PIP2 include neurotransmitter (oxy-choline-type acetylcholine, α1-adrenaline, 5-HT and H1 histamine), some polypeptide hormones (V1 vasopressin, angiotonin II, substance P and thyrotrophin releasing factor), and growth factor (PDGF and T-cell mitogen) (Lu YM et al, 1993). IP3, is a kind of small water solubility molecule, can be diffused rapidly and leave from the cellular membrane.…”

“…The extracellular signals that stimulate the metabolism of PIP2 include neurotransmitter (oxy‐choline‐type acetylcholine, α1‐adrenaline, 5‐HT and H1 histamine), some polypeptide hormones (V1 vasopressin, angiotonin II, substance P and thyrotrophin releasing factor), and growth factor (PDGF and T‐cell mitogen) (Lu YM et al, 1993). IP3, is a kind of small water solubility molecule, can be diffused rapidly and leave from the cellular membrane.…”

Cyanide-stimulated inositol 1,4,5-trisphosphate formation: An intracellular neurotoxic signaling cascade

“…Phospholipase C (PLC) activation is thought to be responsible for the hypoxia-ischemiainduced polyphosphoinositide hydrolysis (15,16). Michell (17) proposed that polyphosphoinositide turnover is one of the earliest intracellular signaling events, preceding and perhaps initiating mobilization of intracellular calcium from storage compartments.…”