Sickle cell disease (SCD), an inherited blood disorder caused by a mutation in the β-globin gene, is characterized by sickle erythrocytes that are ...

Proprioceptive group Ia afferents detect muscle stretch to guide effortless and purposeful movement and make monosynaptic connections with spinal α–motor neurons to mediate reflexes, such as the stret...

Pacemaker myocytes of the sinoatrial (SA) node initiate each heartbeat through coupled voltage and Ca2+ oscillators, but whether ATP supply is regulated on a beat–by–beat schedule in these cells has been unclear. Using genetically encoded sensors targeted to the cytosol and mitochondria, we tracked beat–resolved ATP dynamics in intact mouse SA node and isolated myocytes. Cytosolic ATP rose transiently with each Ca2+ transient and segregated into high– and low–gain phenotypes defined by the Ca2+–ATP coupling slope. Mitochondrial ATP flux adopted two stereotyped waveforms—Mode–1 ″gains″ and Mode–2 ″dips″. Within Mode–1 cells, ATP gains mirrored the cytosolic high/low–gain dichotomy; Mode–2 dips scaled linearly with Ca2+ load and predominated in slower-firing cells. In the intact node, high–gain/Mode–1 phenotypes localized to superior regions and low–gain/Mode–2 to inferior regions, paralleling gradients in rate, mitochondrial volume, and capillary density. Pharmacology placed the Ca2+ clock upstream of ATP production: the HCN channel blocker ivabradine slowed the ATP cycle without changing amplitude, whereas the SERCA pump inhibitor thapsigargin or the mitochondrial uncoupler FCCP abolished transients. Mode–2 recovery kinetics indicate slower ATP replenishment that would favor low–frequency, fluctuation–rich firing in a subset of cells. Together, these findings reveal beat-locked metabolic microdomains in which the Ca2+ clock times oxidative phosphorylation under a local O2 ceiling, unifying vascular architecture, mitochondrial organization, and Ca2+ signaling to coordinate energy supply with excitability. This energetic hierarchy helps explain why some SA node myocytes are more likely to set rate whereas others may widen bandwidth. ### Competing Interest Statement The authors have declared no competing interest. National Heart Lung and Blood Institute, https://ror.org/012pb6c26, HL168874 American Heart Association, https://doi.org/10.58275/AHA.25POST1378853.pc.gr.227467

BACKGROUND: Diabetic hyperglycemia promotes vasoconstriction by activating an ATP-dependent P2Y11L (P2Y11-like receptor)/AC5 (adenylyl cyclase 5)/AKAP5 (A-kinase anchoring protein 5)/PKA (protein kina...

Scientific Article | This protocol describes a procedure for inducing uterine injury in a mouse model, followed by downstream analyses during a subsequent...

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Customized AlphaFold-based modeling of distinct functional states of the hERG channel, a major drug anti-target, significantly improves drug affinity predictions, enhancing cardiac safety screening fo...

The substantial energetic demands on ventricular myocytes imposed by the transport of ions and cross–bridge cycling associated with each heartbeat are well known, yet the spatiotemporal dynamics of AT...