title: Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor.
abstract: The regulated expression of type A gamma-aminobutyric acid (GABA) receptor (GABA(A)R) subunit genes plays a critical role in neuronal maturation and synaptogenesis. It is also associated with a variety of neurological diseases. Changes in GABA(A) receptor alpha1 subunit gene (GABRA1) expression have been reported in animal models of epilepsy, alcohol abuse, withdrawal, and stress. Understanding the genetic mechanism behind such changes in alpha subunit expression will lead to a better understanding of the role that signal transduction plays in control over GABA(A)R function and brings with it the promise of providing new therapeutic tools for the prevention or cure of a variety of neurological disorders. Here we show that activation of protein kinase C increases alpha1 subunit levels via phosphorylation of CREB (pCREB) that is bound to the GABRA1 promoter (GABRA1p). In contrast, activation of protein kinase A decreases levels of alpha1 even in the presence of pCREB. Decrease of alpha1 is dependent upon the inducible cAMP early repressor (ICER) as directly demonstrated by ICER-induced down-regulation of endogenous alpha1-containing GABA(A)Rs at the cell surface of cortical neurons. Taken together with the fact that there are less alpha1gamma2-containing GABA(A)Rs in neurons after protein kinase A stimulation and that activation of endogenous dopamine receptors down-regulates alpha1 subunit mRNA levels subsequent to induction of ICER, our studies identify a transcriptional mechanism for regulating the cell surface expression of alpha1-containing GABA(A)Rs that is dependent upon the formation of CREB heterodimers.
authors.affiliation: Laboratory of Translational Epilepsy, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Hu
authors.forename: Ingrid V
authors.initials: IV
authors.lastname: Lund
authors.forename: Maria C
authors.initials: MC
authors.lastname: Gravielle
authors.forename: David H
authors.initials: DH
authors.lastname: Farb
authors.forename: Amy R
authors.initials: AR
authors.lastname: Brooks-Kayal
authors.forename: Shelley J
authors.initials: SJ
authors.lastname: Russek
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000473:pathology; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D004827:Epilepsy / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D020218:Response Elements; D013574:Synaptosomes / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C497412:Crem protein, rat; C546242:Gabra1 protein, rat; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D051786:Cyclic AMP Response Element Modulator; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C