J. Biol. Chem., Vol. 262, Issue 30, 14549-14554, Oct, 1987
Potassium depletion selectively inhibits sustained diacylglycerol formation from phosphatidylinositol in angiotensin II-stimulated, cultured vascular smooth muscle cells
P Delafontaine, KK Griendling, MA Gimbrone Jr and RW Alexander
Department of Medicine, Harvard Medical School, Massachusetts.
Potassium depletion decreases blood pressure in vivo and blunts the pressor
response to angiotensin II (ang II) without down-regulating the receptor.
In cultured rat aortic smooth muscle cells, the ang II- induced signaling
sequence is biphasic with rapid hydrolysis of the polyphosphoinositides
producing an early (15 s) diacylglycerol (DG) peak and a transient rise in
inositol trisphosphate (IP3) and more delayed phosphatidylinositol (PI)
hydrolysis resulting in sustained DG formation (peak at 5 min). Exposure of
intact vascular smooth muscle cells to low potassium growth medium for 24 h
or acutely potassium- depleting cells with nigericin causes selective,
marked inhibition of late DG formation (5-min peak inhibited by 60 +/- 8%
and 84 +/- 7%, respectively). The early cell response, namely
polyphosphoinositide hydrolysis, inositol bis- and trisphosphate production
and the 15-s DG peak, is not affected. Analysis of 125I-ang II-binding data
reveals no significant differences in either receptor number or binding
affinity (Kd) in potassium-depleted cells. Together with its marked
inhibitory effect on sustained ang II-induced DG formation, acute potassium
depletion effectively blocks internalization of 125I-ang II: there is no
significant internalization of the ligand after 5 min at 37 degrees C
versus 64 +/- 7% internalization in control cells. Thus, potassium
depletion does not alter ang II binding or initial membrane signaling in
rat aortic smooth muscle but blocks ligand internalization and selectively
and markedly inhibits the development of direct PI hydrolysis and sustained
diacylglycerol formation. These findings suggest a role for ligand-receptor
processing in generating the sustained cell response and potentially
explain the lower blood pressure and decreased pressor response to ang II
seen in hypokalemic states in vivo. Furthermore, the ability of K+
depletion to alter secondary signal generation may provide insight into the
mechanisms underlying the K+ dependence of a variety of cell functions.
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