Muscarinic acetylcholine receptors induce the expression of the immediate early growth regulatory gene CYR61.
In brain, muscarinic acetylcholine receptors (mAChRs) modulate neuronal functions including long term potentiation and synaptic plasticity in neuronal circuits that are involved in learning and memory formation. To identify mAChR-inducible genes, we used a differential display approach and found that mAChRs rapidly induced transcription of the immediate early gene CYR61 in HEK 293 cells with a maximum expression after 1 h of receptor stimulation. CYR61 is a member of the emerging CCN gene family that includes CYR61/CEF10, CTGF/FISP-12, and NOV; these encode secretory growth regulatory proteins with distinct functions in cell proliferation, migration, adhesion, and survival. We found that CYR61, CTGF, and NOV were expressed throughout the human central nervous system. Stimulation of mAChRs induced CYR61 expression in primary neurons and rat brain where CYR61 mRNA was detected in cortical layers V and VI and in thalamic nuclei. In contrast, CTGF and NOV expression was not altered by mAChRs neither in neuronal tissue culture nor rat brain. Receptor subtype analyses demonstrated that m1 and m3 mAChR subtypes strongly induced CYR61 expression, whereas m2 and m4 mAChRs had only subtle effects. Increased CYR61 expression was coupled to mAChRs by both protein kinase C and elevations of intracellular Ca(2+). Our results establish that CYR61 expression in mammalian brain is under the control of cholinergic neurotransmission; it may thus be involved in cholinergic regulation of synaptic plasticity.
Albrecht
C
C
Center for Molecular Neurobiology Hamburg, University of Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
von Der Kammer
H
H
Mayhaus
M
M
Klaudiny
J
J
Schweizer
M
M
Nitsch
R M
RM
D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D055513:Connective Tissue Growth Factor; D055515:Cysteine-Rich Protein 61; D018076:DNA, Complementary / Q000737:chemistry; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D055514:Nephroblastoma Overexpressed Protein; D009856:Oncogene Proteins, Viral / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051381:Rats; D011976:Receptors, Muscarinic / Q000145:classification / Q000502:physiology*; D014158:Transcription, Genetic
C501848:CCN1 protein, human; C501849:CCN1 protein, rat; C526317:CCN2 protein, human; C526316:CCN2 protein, rat; C526319:CCN3 protein, human; D055515:Cysteine-Rich Protein 61; D018076:DNA, Complementary; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055514:Nephroblastoma Overexpressed Protein; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D011976:Receptors, Muscarinic; D055513:Connective Tissue Growth Factor