Ca2+/calmodulin-dependent protein kinase IV links group I metabotropic glutamate receptors to fragile X mental retardation protein in cingulate cortex.
Fragile X syndrome is caused by a lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, persistent pain, and mental disorders. Our recent study has shown that activation of Group I mGluR up-regulated FMRP in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions; Ca(2+) signaling pathways could be involved in the regulation of FMRP by Group I mGluRs. In this study we demonstrate that stimulating Group I mGluRs activates Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) in ACC neurons. In ACC neurons of adult mice overexpressing CaMKIV, the up-regulation of FMRP by stimulating Group I mGluR is enhanced. The enhancement occurs at the transcriptional level as the Fmr1 mRNA level was further elevated compared with wild-type mice. Using pharmacological approaches, we found that inhibition of CaMKIV could attenuate the up-regulation of FMRP by Group I mGluRs. CaMKIV contribute to the regulation of FMRP by Group I mGluRs probably through cyclic AMP-responsive element binding protein (CREB) activation, as manipulation of CaMKIV could simultaneously cause the change of CREB phosphorylation induced by Group I mGluR activation. Our study has provided strong evidence for CaMKIV as a molecular link between Group I mGluRs and FMRP in ACC neurons and may help us to elucidate the pathogenesis of fragile X syndrome.
Wang
Hansen
H
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
Fukushima
Hotaka
H
Kida
Satoshi
S
Zhuo
Min
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006179:Gyrus Cinguli / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
D002118:Calcium; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D000242:Cyclic AMP; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C517683:CAMK4 protein, human