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Vol. 291, Issue 3, 1242-1249, December 1999
Department of Veterinary and Comparative Anatomy, Pharmacology and
Physiology, College of Veterinary Medicine, Washington State
University, Pullman, Washington
125I-Angiotensin (Ang) IV and 125I-divalinal
Ang IV [AT receptor subtype 4 (AT4)] receptor agonist and
putative antagonist, respectively] were used to characterize the
AT4 receptor in Mardin-Darby bovine kidney epithelial cells
(MDBK cell line). Both 125I-Ang IV and
125I-divalinal Ang IV bound to a single high-affinity site
(KD = 1.37 and 1.01 nM, respectively)
and to a comparable density of binding sites
(Bmax = 1335 and 1407 fmol/mg protein,
respectively). Competition of either radiolabeled ligand with several
Ang related peptides demonstrated similar displacement affinities in
the following affinity order: Ang IV = divalinal Ang IV > Ang III > Ang II > losartan = PD 123177. Guanosine-5'-O-(3-thio)triphosphate or sulfhydryl reducing agents did not affect the binding of either radiolabeled ligand. Brief exposure of MDBK cells to Ang IV or divalinal Ang IV (0.1 nM to 1 µM) caused a concentration-dependent rise in intracellular calcium concentration levels with a reduced calcium response observed with Ang IV at micromolar concentrations. These results indicate that
Ang IV and divalinal Ang IV bind with high affinity to the same
receptor and that the MDBK AT4 receptor is not coupled to a
classic G protein, nor are sulfhydryl bonds important in regulation of
receptor affinity. The MDBK AT4 receptor appears to be
pharmacologically similar to that described in nonrenal tissues.
Functional studies suggest that AT4 receptor activation can
increase intracellular calcium concentration levels in MDBK cells and
that divalinal Ang IV possesses agonist activity with respect to this
particular intracellular signaling system.
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