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Vol. 55, Issue 1, 142-149, January 1999
Subunits of Heterotrimeric G Proteins in Vascular Smooth
Muscle Cells
Department of Medicine, Division of Cardiology, Emory University,
Atlanta, Georgia
In cultured vascular smooth muscle cells (VSMCs), activation of
phospholipase D (PLD) by angiotensin II (Ang II) represents a major
source of sustained generation of second messengers. Understanding the
molecular mechanisms controlling activation of this pathway is
essential to clarify the complexities of Ang II signaling, but the most
proximal mechanisms coupling AT1 receptors to PLD have not
been defined. Here we examine the role of heterotrimeric G proteins in
AT1 receptor-PLD coupling. In alpha-toxin permeabilized VSMCs, GTP
S enhanced Ang II-stimulated PLD activation. In intact cells, Ang II activation of PLD was pertussis toxin-insensitive and was
not additive with sodium fluoride, a cell-permeant activator of
heterotrimeric G proteins, indicating that AT1 receptor-PLD coupling requires pertussis toxin-insensitive heterotrimeric G proteins. Ang II-stimulated PLD activity was significantly inhibited in
VSMCs electroporated with anti-G
antibody (56 ± 5%) and in cells overexpressing the G-binding region of the carboxyl
terminus of beta-adrenergic receptor kinase1 (79 ± 8%),
suggesting a critical role for G in PLD activation by Ang II.
This effect may be mediated by pp60c-src, because in
beta-adrenergic receptor kinase1 overexpressing cells, pp60c-src activation was inhibited, and in normal cells
anti-pp60c-src antibody inhibited Ang II-stimulated PLD
activity. G
12 may also contribute to AT1
receptor-PLD coupling because electroporation of
anti-G12 antibody significantly inhibited PLD activity,
whereas anti-Gi and Gq/11 antibodies had
no effect. Furthermore, electroporation of anti-RhoA antibody also
attenuated Ang II-induced PLD activation, suggesting a role for small
molecular weight G protein RhoA in this response. Thus, we provide
evidence here that G as well as G12 subunits
mediate AT1 receptor coupling to tonic PLD activation via
pp60c-src-dependent mechanisms, and that RhoA is involved
in these signaling pathways in rat VSMCs. These results may provide
insight into the molecular mechanisms underlying the highly organized,
complex, chronic signaling programs associated with vascular smooth
muscle growth and remodeling in response to Ang II.
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