INCREASED EXPRESSION OF ADENYLYLCYCLASE TYPE-VI PROPORTIONATELY INCREASES BETA-ADRENERGIC RECEPTOR-STIMULATED PRODUCTION OF CAMP IN NEONATAL RAT CARDIAC MYOCYTES
Mh. Gao et al., INCREASED EXPRESSION OF ADENYLYLCYCLASE TYPE-VI PROPORTIONATELY INCREASES BETA-ADRENERGIC RECEPTOR-STIMULATED PRODUCTION OF CAMP IN NEONATAL RAT CARDIAC MYOCYTES, Proceedings of the National Academy of Sciences of the United Statesof America, 95(3), 1998, pp. 1038-1043
Cellular content of cAMP generated by activation of adenylylcyclase (A
C; EC 4.6.1.1) is a key determinant of functional responsiveness in th
e heart and other tissues, We have tested two hypotheses regarding the
relationship between AC content and beta-adrenergic receptor (beta AR
)mediated signal transduction in cardiac myocytes, First, that AC cont
ent limits adrenergic signal transduction, and, second, that increased
AC, independent of (beta AR) number and G-protein content, yields a p
roportional increase in beta AR-mediated transmembrane signaling, We u
sed recombinant adenovirus to increase AC isoform VI (AC(VI)) expressi
on in neonatal cardiac myocytes, Cells that overexpressed AC(VI) respo
nded to agonist stimulation with marked increases in cAMP production i
n proportion to protein expressed, In parallel experiments performed o
n cells transfected with lacZ (control) or AC(VI), [H-3]forskolin bind
ing, used to assess AC protein expression, was amplified 6-fold, while
beta AR-stimulated cAMP production from these cells was increased 7-f
old. No changes in beta AR number, or in the heterotrimeric GTP-bindin
g proteins, Gas or Gait, were observed, Previous studies indicate that
increased cardiac expression of beta AR or Gas does not yield proport
ional increases in transmembrane adrenergic signaling, In contrast, th
e current data demonstrate that increased AC(VI) expression provides a
proportional increase in beta-adrenergic signal transduction, Our res
ults show that the amount of AC sets a limit on transmembrane beta-adr
energic signaling, We speculate that similar functional responses are
possible in other cell types in which AC plays an important physiologi
cal role.