Im. Bird et al., HORMONAL-REGULATION OF ANGIOTENSIN-II TYPE-1 RECEPTOR EXPRESSION AND AT(1)-R MESSENGER-RNA LEVELS IN HUMAN ADRENOCORTICAL-CELLS, Endocrine research, 21(1-2), 1995, pp. 169-182
Human adrenocortical H295R cells express AII receptors which are predo
minantly of the AT(1) but not AT(2) subclass. These receptors are func
tionally coupled to phosphoinositidase C in a manner similar to that s
een in fetal human, sheep and bovine adrenocortical cells. Treatment o
f H295R cells with forskolin or dbcAMP to activate the protein kinase
A pathway caused a rapid (maximal by 3 h) and sustained decrease in AT
(1)-R mRNA levels which in turn preceded a time-dependent (maximal by
12 h) and dose-dependent loss of [I-125]AII binding and phosphoinositi
dase G activation on subsequent AII challenge. Thus, both decreased AT
(1)-R mRNA levels and functional receptor expression appear to paralle
l each other in response to activation of protein kinase A. Activation
of the Ca2+/protein kinase G pathways by treatment with AII also caus
ed a rapid (maximal by 3 h) and dose-dependent loss in AT(1)-R mRNA, b
ut mRNA levels subsequently rose again, approaching control levels by
36 h. Treatment with All for 48 h had little effect on either [I-125]A
II binding or the subsequent phosphoinositidase C response. The effect
of AII, but not forskolin, was blocked by the presence of cycloheximi
de. The action of AII on AT(1)-R mRNA was probably mediated through bo
th protein kinase C and Ca2+-sensitive protein kinases as the effect a
t 4 h was not completely reproduced by phorbol ester alone, but was fu
lly reproduced by a combination of phorbol eater and Ca2+ ionophore. H
owever, increased Ca2+ influx alone, due to treatment with BAYK8644 or
elevated extracellular K+, also resulted in a decrease in AT(1)-R mRN
A levels. Thus in the H295R cell, control of AT(1)-R expression appear
s to be complex, being achieved at least in part through control of th
e level of AT(1)-R mRNA by multiple independent signaling pathways inc
luding protein kinase A, protein kinase C and Ca2+.