In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors.
Glycogen synthase kinase-3 (GSK3), which is inhibited by serine-phosphorylation, is involved in the neuropathology of Alzheimer's disease (AD). We tested if the two therapeutic strategies used for AD, inhibition of acetylcholinesterase and of N-methyl-D-aspartate (NMDA) receptors, modulate the phosphorylation state of the two isoforms of GSK3 in mouse brain. Large, rapid increases in the levels of phospho-Ser21-GSK3alpha and phospho-Ser9-GSK3beta occurred in mouse hippocampus, cerebral cortex, and striatum after treatment of mice with the muscarinic agonist pilocarpine or the acetylcholinesterase inhibitor physostigmine. Treatment with memantine, an NMDA receptor antagonist, also increased the serine-phosphorylation of both GSK3 isoforms in mouse brain. Co-administration of physostigmine and memantine increased serine-phosphorylated GSK3 levels equally to that achieved by either agent alone, indicating that the actions of these two drugs converge on overlapping pools of GSK3. Thus, drugs in each class of therapeutic agents used for AD have the common property of increasing the regulatory serine-phosphorylation of GSK3 within common pools of the enzyme.
De Sarno
Patrizia
P
Department of Psychiatry and Behavioral Neurobiology, 1720 Seventh Ave. South, Sparks Center 1057, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Bijur
Gautam N
GN
Zmijewska
Anna A
AA
Li
Xiaohua
X
Jope
Richard S
RS
D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D038362:Glycogen Synthase Kinase 3; D008297:Male; D008559:Memantine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D010830:Physostigmine / Q000008:administration & dosage; D010862:Pilocarpine / Q000008:administration & dosage; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014018:Tissue Distribution
D002800:Cholinesterase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D010862:Pilocarpine; D010830:Physostigmine; D038362:Glycogen Synthase Kinase 3; D000110:Acetylcholinesterase; D000109:Acetylcholine; D008559:Memantine