AJP - Renal Physiology, Vol 253, Issue 3 401-F407, Copyright © 1987 by American Physiological Society
Effects of cadmium on canine renal cortical adenylate cyclase
U. Lundberg, C. L. Milanes, N. Pernalete, J. R. Weisinger, N. E. Contreras, V. Paz-Martinez and E. Bellorin-Font
The present studies examine the effects of cadmium (Cd2+) on adenylate
cyclase activity in basolateral renal cortical membranes from normal dogs.
Cd2+, in the dose range of 1 to 200 microM caused a dose-dependent
inhibition of adenylate cyclase activity due to competitive inhibition with
respect to the allosteric activator Mg2+ (increase in the Kact for Mg2+
from 13.8 to 37.2 mM). In addition, increasing Cd2+ concentrations from 0
to 25 microM resulted in a purely competitive inhibition with respect to
ATP. The Km for ATP increased from 61 to 128 microM. When Mn2+ at a
concentration of 20 mM was substituted for Mg2+, Cd2+ maintained its
inhibitory effect at concentrations lower than 25 microM. At higher
concentrations it stimulated enzyme activity in a dose-dependent fashion.
In the absence of other divalent cations Cd2+ was a potent stimulator of
basal adenylate cyclase activity, far more potent than the physiological
activator of the system Mg2+. Kact for Cd2+ was 1.0 mM (Kact for Mg2+ 20
mM), whereas the Vmax showed a fourfold increase compared with the
Mg2+-stimulated membranes. However, under these conditions, synthetic
bovine parathyroid hormone (1-34) or 5'-guanylylimidodiphosphate did not
stimulate adenylate cyclase. It is concluded that Cd2+ behaves as a partial
agonist in this system, due to its ability to form a new enzymatic
substrate complex: Cd-ATP, which competes with the physiological substrate
Mg-ATP at the catalytic site of the enzyme. In addition, Cd2+ in the
absence of other divalent cation stimulates basal enzyme activity,
presumably through interaction at an additional site, closely related to
the allosteric metal regulatory site of this enzyme system.
