Beta-adrenergic receptor agonists and cyclic nucleotide phosphodiesterase inhibitors: shifting the focus from inotropy to cyclic adenosine monophosphate
Matthew A. Movsesian, MDa
a Salt Lake City VA Medical Center, University of Utah School of Medicine, Salt Lake City, Utah, USA
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Figure 1 Cyclic adenosine monophosphate (cAMP)-mediated signaling in cardiac myocytes. Cyclic adenosine monophosphate generated by adenylate cyclase activates cAMP-dependent protein kinase (PK-A), some of which is in the cytosol and some of which is bound to intracellular membranes by anchoring proteins (AKAPs). Proteins phosphorylated by cAMP-dependent protein kinase include L-type and ryanodine (Ry)-sensitive Ca2+ channels in the sarcolemma and sarcoplasmic reticulum, respectively; phospholamban (PL), which interacts with the Ca2+-transporting adenosine triphosphatase (SERCA2) of the sarcoplasmic reticulum; troponin (Tn) I, complexed with troponin C, troponin T, tropomyosin (TM) and actin in the thin filaments, and transcription factors such as cAMP-response element-binding protein (CREB), whose phosphorylation is dependent upon the translocation of cAMP-dependent protein kinase from the cytosol to the nucleus. ATP = adenosine triphosphate.
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Figure 2 Alternative interpretations of the results of clinical trials of beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors. The "conventional" interpretation is that increasing intracellular cyclic adenosine monophosphate (cAMP) content causes a short-term increase in contractility that causes a reduction in long-term survival. The alternative interpretation proposed herein is that the increase in intracellular cAMP content may increase contractility and increase mortality through separate mechanisms.
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Figure 3 Schematic representation of the substrates of cyclic adenosine monophosphate (cAMP)-dependent protein kinase. Substrates of cAMP-dependent protein kinase may be thought of as belonging to the subset whose phosphorylation contributes to the increased mortality seen with beta-adrenergic receptor agonists and PDE3 inhibitors and/or to the subset whose phosphorylation contributes to increased contractility. The extent of overlap between the two subsets is unknown.
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Figure 4 Selective inhibition of dephosphorylation. Four substrates of cyclic adenosine monophosphate (cAMP)-dependent protein kinase—troponin I (TnI), phospholamban (PL), glycogen synthase (Gly Syn) and cAMP-response element-binding protein (CREB)—are represented hypothetically coupled to separate protein phosphatases (designated PP-T, PP-P, PP-G and PP-C). Selective inhibition of PP-T would result in a selective increase in the phosphorylation of troponin I. PK-A = protein kinase.
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