Changes in type VI adenylyl cyclase isoform expression correlate with a decreased capacity for cAMP generation in the aging ventricle.

Abstract

We investigated the developmental regulation of the 13-adrenergic receptor-G,-adenylyl cyclase pathway in myocardial membranes from fetal, neonatal, adult, and mature adult rats by measuring the density of the /3-adrenergic receptor and the activities of the stimulatory guanine nucleo- of mRNA coding for Gs,, no significant differences were seen among the developmental stages studied. Unlike G,,, the inhibitory protein Gi,(i was subject to developmental regulation; however, concomitant evaluation of Gi,2 levels both by ADP-ribosylation with pertussis toxin and by immunoblotting showed the greatest amount in the fetus (0.82±0.07 pmol/mg) and the neonate (0.51±0.1 pmol/mg). The adult and mature adult both contained 0.09±0.02 pmol/mg. Also, the steadystate Gia2 mRNA level paralleled the amount of protein.Similarly, the level of type V mRNA coding for adenylyl cyclase was greater in the mature adult than in the fetal and neonatal stages. In contrast, the level of type VI adenylyl cyclase mRNA decreased with age, paralleling the decline in the functional activity of adenylyl cyclase with age. Taken together, these data suggest that the age-related changes in the activity of the myocardial f3-adrenergic receptor-G,-adenylyl cyclase pathway is not primarily regulated by alteration in the level of GS or Gi but by the density of f3-adrenergic receptors and by the activity of the catalyst adenylyl cyclase. In particular, steady-state mRNA measurements show that a decrease in the content of the type VI isoform of adenylyl cyclase correlates with a decrease in catalytic activity with age. (Circ Res. 1994;74:596-603.)

Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload

“…In part, differences in results can be ascribed to different isoforms of AC, which are expressed in the heart. There are nine major mammalian isoforms of AC, with type 6 AC being the major fetal cardiac AC isoform, and type 5 AC, the major cardiac isoform in the adult (23,24). Overexpressing type 6 AC results in maintained cardiac function and no myocardial fibrosis, even in 19-mo-old mice (20).…”

Pharmacological Stimulation of Type 5 Adenylyl Cyclase Stabilizes Heart Rate Under Both Microgravity and Hypergravity Induced by Parabolic Flight

“…AC consists of 9 mammalian transmembrane isoforms that differ in tissue distribution (3,5), with type 6 AC (AC6) being the major fetal cardiac AC isoform, and AC5, the major cardiac isoform in adults (27,28). All isoforms are stimulated by Gs, but AC5 and AC6 are the only Gi-and Ca…”

Determination and cellular localization of adenylyl cyclase isozymes expressed in embryonic chick heart

“…It should be remembered that the myocytes are embryonic, and that the relative amounts of the two messages may vary during development. Northern blots of mRNA prepared from rat hearts of different ages suggest that the expression of type V adenylyl cyclase increases with age while that for type VI decreases [22]. As both in situ hybridization and Northern blots measure message, not protein, and mRNA and protein are not necessarily directly proportional, measurements of the individual isozymes will be needed before their contributions to total adenylyl cyclase activity can be evaluated.…”

“…Therefore, we can not conclude with confidence that chick ventricular myocytes do not contain any other adenylyl cyclase isoforms. Importantly, other workers reported that type IV and VII mRNAs in rat cardiac tissues are difficult to detect by Northern blot analysis using poly(A) ÷ RNA; easily detectable levels of type V and VI mRNAs were reported by the same workers [22].…”