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J. Biol. Chem., Vol. 276, Issue 4, 2474-2479, January 26, 2001

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The M₃ Muscarinic Acetylcholine Receptor Expressed in HEK-293 Cells Signals to Phospholipase D via G₁₂ but Not G_q-type G Proteins
REGULATORS OF G PROTEINS AS TOOLS TO DISSECT PERTUSSIS TOXIN-RESISTANT G PROTEINS IN RECEPTOR-EFFECTOR COUPLING^*

Ulrich Rümenapp^§, Melanie Asmus, Helge Schablowski, Markus Woznicki, Li Han, Karl H. Jakobs, Mercedeh Fahimi-Vahid^¶, Christina Michalek^¶, Thomas Wieland^¶, and Martina Schmidt

From the  Institut für Pharmakologie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany and the ^¶ Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, D-20246 Hamburg, Germany

The M₃ muscarinic acetylcholine receptor (mAChR) expressed in HEK-293 cells couples to G_q and G₁₂ proteins and stimulates phospholipase C (PLC) and phospholipase D (PLD) in a pertussis toxin-insensitive manner. To determine the type of G protein mediating M₃ mAChR-PLD coupling in comparison to M₃ mAChR-PLC coupling, we expressed various G proteins and regulators of the G protein signaling (RGS), which act as GTPase-activating proteins for G_q- or G₁₂-type G proteins. PLD stimulation by the M₃ mAChR was enhanced by the overexpression of G₁₂ and G₁₃, whereas the overexpression of G_q strongly increased PLC activity without affecting PLD activity. Expression of the RGS homology domain of Lsc, which acts specifically on G₁₂ and G₁₃, blunted the M₃ mAChR-induced PLD stimulation without affecting PLC stimulation. On the other hand, overexpression of RGS4, which acts on G_q- but not G₁₂-type G proteins, suppressed the M₃ mAChR-induced PLC stimulation without altering PLD stimulation. We conclude that the M₃ mAChR in HEK-293 cells apparently signals to PLD via G₁₂- but not G_q-type G proteins and that G protein subtype-selective RGS proteins can be used as powerful tools to dissect the pertussis toxin-resistant G proteins and their role in receptor-effector coupling.

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