Protein kinase C activity blocks neuropeptide Y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus.
The unbalanced excitatory/inhibitory neurotransmitter function in the neuronal network afflicted by seizures is the main biochemical and biophysical hallmark of epilepsy. The aim of this work was to identify changes in the signaling mechanisms associated with neuropeptide Y (NPY)-mediated inhibition of glutamate release that may contribute to hyperexcitability. Using isolated rat hippocampal nerve terminals, we showed that the KCl-evoked glutamate release is inhibited by NPY Y2 receptor activation and is potentiated by the stimulation of protein kinase C (PKC). Moreover, we observed that immediately after status epilepticus (6 h postinjection with kainate, 10 mg/kg), the functional inhibition of glutamate release by NPY Y2 receptors was transiently blocked concomitantly with PKC hyperactivation. The pharmacological blockade of seizure-activated PKC revealed again the Y2 receptor-mediated inhibition of glutamate release. The functional activity of PKC immediately after status epilepticus was assessed by evaluating phosphorylation of the AMPA receptor subunit GluR1 (Ser-831), a substrate for PKC. Moreover, NPY-stimulated [35S]GTPgammaS autoradiographic binding studies indicated that the common target for Y2 receptor and PKC on the inhibition/potentiation of glutamate release was located downstream of the Y2 receptor, or its interacting G-protein, and involves voltage-gated calcium channels.
Silva
Ana P
AP
Institute of Pharmacology and Therapeutics, University of Coimbra, 3004-504 Coimbra, Portugal.
Lourenço
Joana
J
Xapelli
Sara
S
Ferreira
Raquel
R
Kristiansen
Heidi
H
Woldbye
David P D
DP
Oliveira
Catarina R
CR
Malva
João O
JO
D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009478:Neuropeptide Y / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013226:Status Epilepticus / Q000473:pathology*
D009478:Neuropeptide Y; D018698:Glutamic Acid; D011493:Protein Kinase C