DCP-LA stimulates AMPA receptor exocytosis through CaMKII activation due to PP-1 inhibition.
The linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA) activated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) by inhibiting protein phosphatase-1 (PP-1). DCP-LA induced a transient huge facilitation of synaptic transmission monitored from the CA1 region of rat hippocampal slices, which was largely inhibited by the CaMKII inhibitor KN-93. DCP-LA potentiated kainate-evoked whole-cell membrane currents for Xenopus oocytes expressing alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors composed of the GluR1, GluR3, GluR1/GluR2, GluR1/GluR3, and GluR1/GluR2/GluR3 subunits, and the potentiation was significantly inhibited by KN-93. A similar potentiation was still found with mutant GluR1 (S831A) receptor lacking CaMKII phosphorylation site. The GluR1 and GluR2 subunits formed AMPA receptors in the rat hippocampus, and DCP-LA increased expression of both the subunits on the plasma membrane. The DCP-LA action was blocked by KN-93 and the exocytosis inhibitor botulinum toxin type A, but not by the endocytosis inhibitor phenylarsine oxide. DCP-LA, thus, appears to activate CaMKII through PP-1 inhibition, that stimulates AMPA receptor exocytosis to increase expression of the receptors on the plasma membrane, responsible for potentiate AMPA receptor responses and facilitation of hippocampal synaptic transmission.
Kanno
Takeshi
T
Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
Yaguchi
Takahiro
T
Nagata
Tetsu
T
Tanaka
Akito
A
Nishizaki
Tomoyuki
T
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002210:Caprylates / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology; D008297:Male; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects
C506022:8-(2-(2-pentyl-cyclopropylmethyl)cyclopropyl)octanoic acid; D002210:Caprylates; D018091:Receptors, AMPA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054645:Protein Phosphatase 1