Regulation of transcription factor phosphorylation by metabotropic glutamate receptor-associated signaling pathways in rat striatal neurons.
The group I metabotropic glutamate receptors (mGluRs) are positively coupled to phospholipase C. Through phospholipase C, group I mGluR activation increases intracellular concentrations of diacylglycerol which is known as a strong activator of protein kinase C (PKC). This study investigated the putative role of PKC in the regulation of transcription factor phosphorylation induced by group I mGluR activation in the rat striatum in vivo. We found that the group I agonist 3,5-dihydroxyphenylglycine (DHPG) injected into the dorsal striatum (caudate-putamen) increased phosphorylation of the two transcription factors, cAMP response element-binding protein (CREB) and Elk-1, and extracellular signal-regulated kinase 1/2 (ERK1/2) in the injected striatum. Inhibition of PKC with GF109203X significantly attenuated DHPG-stimulated CREB, Elk-1, and ERK1/2 phosphorylation. Activation of PKC with intracaudate injection of 12-O-tetradecanoylphorbol-13-acetate (TPA) mimicked DHPG actions in facilitating the phosphorylation of CREB, Elk-1, and ERK1/2. Blockade of N-methyl-D-aspartate (NMDA) glutamate receptors with the non-competitive antagonist MK801 or the competitive antagonist AP5 attenuated TPA-induced CREB, Elk-1, and ERK1/2 phosphorylation. Similarly, inhibition of Ca(2+)/calmodulin-dependent protein kinases (CaMK) with KN62 also resulted in a significant attenuation of TPA induction of the three phosphoproteins. The data obtained from this study indicate that selective activation of PKC is needed for the group I agonist-induced CREB, Elk-1, and ERK1/2 phosphorylation in striatal neurons. Activated PKC may, at least in part, facilitate the phosphorylation of transcription factors via an NMDA/CaMK-sensitive pathway.
Choe
E S
ES
Division of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, M3-C225, Kansas City, MO 64108, USA.
Wang
J Q
JQ
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*
D018094:Receptors, Metabotropic Glutamate; D014157:Transcription Factors; C104077:metabotropic glutamate receptor type 1; D011493:Protein Kinase C