Effect of hippocampal sympathetic ingrowth and cholinergic denervation on hippocampal phospholipase C activity and G-protein function.
Following cholinergic denervation of the hippocampal formation, via medial septal lesions, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus. In previous studies, we have found that hippocampal sympathetic ingrowth and cholinergic denervation alone (animals with concurrent medial septal lesions and superior cervical ganglionectomy) alter phosphoinositide turnover and muscarinic cholinergic receptors in such a way as to suggest an alteration in coupling between the muscarinic cholinergic receptors and phosphoinositol turnover. To test this hypothesis we examined the effect of hippocampal sympathetic ingrowth and cholinergic denervation on phospholipase C activity, G-protein function and the whole receptor complex by measuring the amount of phosphoinositide hydrolysed in hippocampal membranes of the rat. Neither hippocampal sympathetic ingrowth nor cholinergic denervation was found to alter phospholipase C activity when activated by increasing concentrations of Ca2+. In dorsal hippocampus, cholinergic denervation, when compared to hippocampal sympathetic ingrowth and controls, was found to decrease the amount of phosphoinositol hydrolysed when stimulated with the GTP analog, guanosine-5'-O-(3-thiotriphosphate). When guanosine-5'-O-(3-thiotriphosphate) plus carbachol (1 mM) was utilized to stimulate the entire receptor complex, phosphoinositol hydrolysis was found to be decreased in the cholinergic denervation group as compared to both hippocampal sympathetic ingrowth and control groups. This effect was maximum at 3 microM guanosine-5'-O-(3-thiotriphosphate). These results suggest that both hippocampal sympathetic ingrowth and cholinergic denervation affect the efficiency of coupling between the muscarinic cholinergic receptors and phosphoinositol turnover, with cholinergic denervation decreasing and hippocampal sympathetic ingrowth "normalizing" efficiency. Further, they suggest that the G-protein is the site at which hippocampal sympathetic ingrowth and cholinergic denervation mediate their effects. The results of these experiments are also discussed within the context of recent findings demonstrating G-protein abnormalities in Alzheimer's disease.
Kolasa
K
K
Alzheimer's Disease Center, VA Medical Center, Birmingham, AL, USA.
Harrell
L E
LE
Parsons
D S
DS
D000320:Adrenergic Fibers / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002799:Cholinergic Fibers / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D006868:Hydrolysis; D008297:Male; D010277:Parasympathomimetics / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013562:Sympathectomy; D014316:Tritium; D010738:Type C Phospholipases / Q000378:metabolism*
D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002217:Carbachol; D002795:Choline O-Acetyltransferase; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D002118:Calcium