Shaker potassium channel mediates an age-sensitive neurocardiac axis regulating sleep and cardiac function in...

The Shaker (Sh) gene in Drosophila melanogaster encodes a voltage-gated potassium channel that regulates neuronal excitability and is well known for its role in sleep regulation; however, its contribution to cardiac physiology and neurocardiac communication remains insufficiently explored. In this study, we investigated how two Sh-mutations (Sh^mns and Sh⁵) influence heart function and sleep/circadian behaviors to identify potential age-dependent neurocardiac interactions. Cardiac performance and sleep/activity were examined across aging cohorts under normal conditions, circadian disruption, and with or without time-restricted feeding (TRF). Sh^mns mutants exhibited progressive cardiac decline with age, including increased heart period, elevated arrhythmicity, extended systolic and diastolic intervals, reduced contraction rate, and overall impaired cardiac output, along with disorganization of actin-rich myofibrils. These defects paralleled severe sleep loss and hyperactivity, suggesting a tight link between sleep/circadian dysregulation and cardiac impairment. Circadian misalignment further worsened both behavioral and cardiac deficits, whereas TRF partially improved select abnormalities, indicating feeding-time modulation of Sh-related phenotypes. Tissue-specific knockdown of Sh in cardiac and neuronal tissues recapitulated key mutant features, and notably, neuronal knockdown alone impaired cardiac behavior, supporting a functional neurocardiac regulatory axis mediated by Shaker-dependent electrical signaling. Together, these results demonstrate that Shaker channels contribute to an age-sensitive interplay between sleep/circadian regulation and cardiac homeostasis in Drosophila. Although direct extrapolation is limited, parallels with KCNA1-associated cardiac and neuronal abnormalities in humans suggest conserved Kv channel functions in neurocardiac dysfunction. Overall, this study identifies Shaker as a critical mediator of aging-, feeding-, and circadian-sensitive cross-tissue regulation of cardiac function, providing broader insight into mechanisms underlying neurocardiac communication. Our study establishes Shaker as a critical mediator of aging, circadian-sensitive, cross-tissue physiological regulation of cardiac function.