J. Biol. Chem., Vol. 264, Issue 1, 243-250, Jan, 1989
Inhibition of transducin activation and guanosine triphosphatase activity by aluminum ion
JL Miller, CM Hubbard, BJ Litman and TL Macdonald
Department of Biochemistry, School of Medicine, University of Virginia, Charlottesville 22901.
Aluminum ion perturbs the activity of a number of physiologically important
enzymes, including members of a family of guanine nucleotide- binding
proteins (G-proteins). G-proteins couple cellular receptor proteins to a
variety of effector enzymes (including adenylate cyclase, phospholipase C,
and the rod photoreceptor phosphodiesterase). We show herein that
subnanomolar concentrations of free aluminum ion, produced in a carefully
defined and kinetically stable manner through the buffering of total
aluminum at 0.1-1.0 mM with calculated ratios of chelating agents, inhibit
both the receptor-mediated activation and the self-inactivating GTPase
activity of the rod photoreceptor G-protein, Gv. In the presence of 4 X
10(-10) M free aluminum ion, GTPase activity is inhibited from about 25-60%
as the magnesium ion concentration is reduced from 10(-3) to about 5 X
10(-5) M. The principal effect of aluminum ion upon Gv is to inhibit
receptor catalyzed nucleotide exchange. Binding of the GTP analog
5'-guanylyl imidodiphosphate can be reduced by as much as 90% by aluminum
ion following subsaturating rhodopsin stimulation. Aluminum ion can produce
either competitive or mixed noncompetitive inhibition of
rhodopsin-catalyzed Gv activation and GTPase activity, as a function of
whether Gv undergoes single (competitive), or multiple (mixed
noncompetitive) nucleotide exchanges. The rod photoreceptor
phosphodiesterase is only slightly inhibited by similar aluminum ion
activities. Light- and Gv-coupled phosphodiesterase activation exhibits
both a lower maximum rate of cyclic guanosine monophosphate hydrolysis and
a slower inactivation in the presence of aluminum ion activities from about
10(-12) - 10(-10) M. These data suggest that intracellular free aluminum
ion concentrations in the subnanomolar range could markedly affect the
ability of cells to transduce extracellular signals. Interestingly, the
combination of Al3+ and F- to produce the fluoro-aluminate species (AlFx)
also inhibits the GTPase of G-proteins, although the mechanism of
inhibition (e.g. binding to the G-protein.Mg2+.GDP complex) is totally
distinct from that observed for free Al3+ and the overall effect on signal
transduction (e.g. enhanced signal amplification) is in complete opposition
to that observed for free Al3+.
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