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Vol. 62, Issue 5, 983-992, November 2002
Departments of Pharmacology and Medicine, School of Medicine,
University of California, San Diego, La Jolla, California
A number of different agonists activate G protein-coupled
receptors to stimulate adenylyl cyclase (AC), increase cAMP formation, and promote relaxation in vascular smooth muscle. To more fully understand this stimulation of AC, we assessed the expression, regulation, and compartmentation of AC isoforms in rat aortic smooth
muscle cells (RASMC). Reverse transcription-polymerase chain reaction
detected expression of AC3, AC5, and AC6 mRNA, whereas immunoblot
analysis indicated expression of AC3 and AC5/6 protein primarily in
caveolin-rich membrane (cav) fractions relative to noncaveolin (noncav)
fractions. 
1-Adrenergic receptors (AR), 2AR, and Gs were detected in both cav and
noncav fractions, whereas the prostanoid receptors EP2R and
EP4R were excluded from cav fractions. We used an
adenoviral construct to increase AC6 expression. Overexpressed AC6
localized only in noncav fractions. Two-fold overexpression of AC6
caused enhancement of forskolin-, isoproterenol- and prostaglandin
E2-stimulated cAMP formation but no changes in basal levels
of cAMP. At higher levels of AC6 overexpression, basal and adenosine
receptor-stimulated cAMP levels were increased. Stimulation of cAMP
levels by agents that increase Ca2+ in native cells was
consistent with the expression of AC3, but overexpression of AC6, which
is inhibited by Ca2+, blunted the
Ca2+-stimulable cAMP response. These data indicate that: 1)
RASMC express multiple AC isoforms that localize in both caveolin-rich and noncaveolin domains, 2) expression of AC6 in non-caveolin-rich membranes can increase basal levels of cAMP and response to several stimulatory agonists, and 3) Ca2+-mediated regulation of
cAMP formation depends upon expression of different AC isoforms in
RASMC. Compartmentation of GPCRs and AC is different in cardiomyocytes
than in RASMC, indicating that targeting of these components to
caveolin-rich membranes can be cell-specific. Moreover, our results
imply that the colocalization of GPCRs and the AC isoforms they
activate need not occur in caveolin-rich fractions.
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