In sinoatrial node cells (SANC), Ca2+ activates adenylate cyclase (AC) to generate a high basal level of cAMP/protein kinase A (PKA)-dependent phosphorylation of Ca2+ cycling proteins, resulting in spontaneous rhythmic Ca2+ oscillations. These Ca2+ oscillations 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 and to pump Ca2+. We hypothesized that, since nature links ATP-demand to ATP production the both would also be Ca2+-cAMP/PKA dependent in pacemaker cells, and due to its feedforward nature, a decrease in flux through Ca2+-cAMP/PKA signaling axis will result in changes in ATP;This would distinctly differ from ventricular myocytes (VM), which lack this feed-forward basal cAMP/PKA signaling, and in which ATP remains constant when the demand decreases. We perturbed Ca2+-cAMP/PKA signaling and examined the effect on ATP levels in rabbit isolated SANC. VM were used as negative/positive controls. Graded reduction of Ca2+-cAMP/PKA signaling in SANC resulted in graded ATP depletion (r squared=0.96), and decreased oxygen consumption and flavoprotein fluorescence. In contrast, in electrically stimulated (at 3Hz) VM, as expected, ATP remained constant in response to these interventions. Furthermore, preferential ATP production by glycolyisis in SANC did not alter ATP, oxygen consumption and AP firing rate. Blocking SANC contraction without decreasing the rhythmic AP firing rate did not reduce the ATP level. Feed-forward Ca2+-cAMP/PKA signaling that drive spontaneous APs in SANC to is tightly linked to mitochondrial ATP production. Disturbing the Ca-cAMP/PKA signaling that drives the SANC ATP demand pulls the plug on SANC energy supply.
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