Adenylyl cyclase: a new target for heart failure therapeutics.

Abstract

In the early 1960s, Earl Sutherland and his colleagues performed a series of experiments that led to the understanding that the positive inotropic effects of β-adrenergic agonists were mediated by the activation of the enzyme adenylyl cyclase (AC) and the subsequent production of cyclic adenosine monophosphate (cAMP).1 By measuring tissue cAMP levels while simultaneously monitoring the mechanical properties of the heart, these investigators were able to show that cAMP levels increased with extraordinary speed, an increase that correlated directly with increased force of contraction. Subsequent studies demonstrated that AC activity is enhanced through a pathway beginning with ligand binding to β1-adrenergic receptors (β1ARs) and subsequent activation of stimulatory guanine nucleotide–binding signal transduction proteins (Gs). The resultant production of cAMP mediates improvements in both cardiac inotropy and lusitropy via stimulation of cAMP-dependent protein kinase A and the protein kinase A–dependent phosphorylation of key target proteins, including the L-type calcium channel, phospholamban, and troponin I. In the normal heart, activation of the βAR–G protein–AC pathway effects enhanced contractility, which is paramount in facilitating the “flight or fight” response. However, in the failing human heart, profound alterations in multiple components of this βAR–G protein–AC signal transduction cascade reduce cardiac reserve and contribute to decreased exercise response in patients with heart failure.2 Paradoxically, long-term activation of the neurohormonal pathway accelerates the natural history of heart failure. See p 1989 Thus, a therapeutic conundrum has arisen: How can one enhance myocardial contractility while at the same time protecting the heart from the untoward consequences of heightened and continuous adrenergic activation? With the use of transgenic overexpression and gene-targeted knockouts, investigators have demonstrated the potential utility of low levels of β2AR overexpression or inhibition of βAR kinase (βARK) in improving cardiac contractile function without obvious cardiotoxicity (see …