Ca 2+-Regulated-cAMP/PKA Signaling in Cardiac Pacemaker Cells Links ATP Supply to Demand

Abstract

Rationale: In sinoatrial node cells (SANC), Ca2+ activates adenylate cyclase (AC) to generate a high basal level of cAMP-mediated/protein kinase A (PKA)-dependent phosphorylation of Ca2+ cycling proteins. This results in spontaneous sarcoplasmic reticulum-generated rhythmic Ca2+ oscillations during diastolic depolarization, that not only ignite the surface membrane to generate rhythmic action potentials (APs), but, in a feed-forward manner, also activate AC/PKA signaling. ATP is consumed to produce cAMP, to pump Ca2+ and to contract. Objective: Since nature efficiently links ATP-demand to ATP production, we hypothesized that (1) both basal ATP supply and demand in SANC would be Ca2+-cAMP/PKA dependent; and (2) due to its feed-forward nature, a decrease in flux through the Ca2+-cAMP/PKA signaling axis will reduce the basal ATP level. Methods and Results: Graded reduction of basal Ca2+-cAMP/PKA signaling in rabbit SANC, produced graded ATP depletion (r2=0.96), and reduced O2 consumption and flavoprotein fluorescence. Neither inhibition of glycolysis, nor selectively blocking contraction reduced the ATP level. Specific inhibition of mitochondrial Ca2+ flux was without effect, indicating that the cAMP/PKA component rather than Ca2+ directly, links the Ca2+/cAMP-PKA signaling to ATP production. Conclusions: Feed-forward basal Ca2+-cAMP/PKA signaling both consumes ATP to drive spontaneous APs in SANC and is tightly linked to mitochondrial ATP production. Interfering with Ca2+-cAMP/PKA signaling to reduce the SANC ATP demand also “pulls the plug” on SANC ATP supply. This distinctly differs from ventricular myocytes, which lack this feed-forward basal cAMP/PKA signaling, and in which ATP level remains constant when the demand changes.