PT  - JOURNAL ARTICLE
AU  - Shulamith H. Shafer
AU  - Carol L. Williams
TI  - Elevated Rac1 Activity Changes the M<sub>3</sub> Muscarinic Acetylcholine Receptor-Mediated Inhibition of Proliferation to Induction of Cell Death
AID  - 10.1124/mol.65.5.1080
DP  - 2004 May 01
TA  - Molecular Pharmacology
PG  - 1080--1091
VI  - 65
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/65/5/1080.short
4100  - http://molpharm.aspetjournals.org/content/65/5/1080.full
SO  - Mol Pharmacol2004 May 01; 65
AB  - Although muscarinic acetylcholine receptors (mAChRs) regulate proliferation in many cell types, the signaling pathways involved are unclear. The participation of the small GTPases Rac1 and RhoA in M3 mAChR-mediated inhibition of proliferation was investigated by activating M3 mAChRs stably transfected in Chinese hamster ovary cells stably coexpressing hemagglutinin (HA)-tagged wild-type or mutant Rac1 or RhoA proteins. Activation of M3 mAChRs activates both Rac1 and RhoA and inhibits cell proliferation in all cell lines tested. mAChR-mediated inhibition of proliferation is diminished in cells expressing dominant-negative HA-Rac1Asn17 (m3DNRac) but is enhanced in cells expressing HA-Rac1 (m3WTRac) or constitutively active HA-RacVal12 (m3CARac). The activation of mAChRs in m3WTRac and m3CARac cells also induces apoptosis. Expression of wild-type or mutant RhoA proteins does not alter mAChR-mediated inhibition of proliferation. mAChR-induced inhibition of proliferation is abrogated in all cell lines when Gαq/11 signaling is terminated by transient expression of the COOH-terminal fragment of phospholipase C (PLC-β1ct), the NH2-terminal fragment of G protein-coupled receptor kinase, or the regulator of G protein signaling 2. Pretreatment of all cells expressing wild-type or mutant Rac1 proteins with edelfosine, a phosphatidylinositol-specific PLC inhibitor, or Go 6976, which inhibits conventional protein kinase C (PKC) isoforms, diminishes the M3 mAChR's ability to inhibit proliferation. Our results identify Gαq/11, PLC, and PKC as participants in the M3 mAChR-mediated inhibition of cell proliferation. These findings indicate that in the context of high Rac1 activity, but not RhoA activity, M3 mAChR-mediated activation of these participants triggers cell death.