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Vol. 62, Issue 3, 654-659, September 2002
Department of Pharmacology and Toxicology, Faculty of Medicine and
Dentistry, University of Western Ontario, London, Ontario, Canada
RGS2 and RGS4 were studied for their effects as GTPase activating
proteins (GAPs) on receptor-activated Gi in a novel
steady-state assay using membranes from Sf9 cells quadruply infected
with baculoviruses encoding the m2 muscarinic receptor,
G
i2, G
1, and G
2. In the
presence of the muscarinic agonist carbachol, regulator of G protein
signaling 2 (RGS2) and RGS4 each produced up to a 10-fold increase in
agonist-dependent GTPase activity. The observed Km for GTP in this system was increased in
the presence of RGS4. NaCl and KCl inhibited the GAP activities of both
RGS2 and RGS4, although they had no effect on GTPase activity in the
absence of RGS proteins. MgCl2 had a complex effect on
GTPase activity, with optimal RGS2 and RGS4 GAP activities occurring,
respectively, at high micromolar and low millimolar concentrations of
free Mg2+. The concentration dependence of RGS GAP activity
was assessed, and RGS4 was found to be more potent than RGS2 by up to
an order of magnitude. This direct observation confirms a similar
difference in potency found when these two RGS proteins were compared
for their ability to inhibit signaling downstream of Gi
(Heximer et al., 1999). RGS2 yielded Hill coefficients greater than
2.0, suggesting that it may bind in a positively cooperative manner to
oligomeric structures containing more than one G protein. Furthermore,
RGS4 yielded a bell-shaped dose-dependence under low magnesium (0.5 mM)
conditions, which is also consistent with the idea of RGS cooperativity.
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