RACK1 is involved in β-amyloid impairment of muscarinic regulation of GABAergic transmission.
RACK1 (receptor for activated C-kinase 1), an anchoring protein that shuttles activated PKC to cellular membranes, plays an important role in PKC-mediated signal transduction pathways. A significant loss of RACK1 has been found in the brain of aging animals and Alzheimer's disease (AD) patients, which implicates the potential involvement of RACK1 in altered PKC activation associated with dementia. Our previous studies have demonstrated that GABAergic inhibition in prefrontal cortex, which is important for cognitive processes like "working memory", is regulated by muscarinic receptors via a PKC-dependent mechanism, and this effect is impaired by β-amyloid peptide (Aβ). In this study, we found that Aβ oligomers decreased RACK1 distribution in the membrane fraction of cortical neurons. Moreover, overexpression of RACK1 rescued the effect of muscarinic receptors on GABAergic transmission in Aβ-treated cortical cultures in vitro and Aβ-injected cortical neurons in vivo. These results suggest that the Aβ-induced loss of RACK1 distribution in the cell membrane may underlie the Aβ impairment of muscarinic regulation of PKC and GABAergic transmission. Thus, RACK1 provides a potential therapeutic target that can restore some of the impaired cellular processes by Aβ.
Liu
Wenhua
W
Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
Dou
Fei
F
Feng
Jian
J
Yan
Zhen
Z
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004622:Embryo, Mammalian; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000075370:Receptors for Activated C Kinase; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018679:Cholinergic Agonists; D010446:Peptide Fragments; C550931:RACK1 protein, rat; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D011976:Receptors, Muscarinic; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D002217:Carbachol; D011493:Protein Kinase C; D019204:GTP-Binding Proteins