Functional coupling between Piezo1 and SK channels in the paraventricular nucleus regulates sympathetic nerve activity.

Excessive sympathetic overactivation serves as a core pathological mechanism underlying the initiation and progression of cardiovascular diseases such as hypertension. The hypothalamic paraventricular nucleus (PVN) acts as a pivotal integrative nucleus of the sympathetic center, and functional imbalance of neuronal ion channels within this nucleus constitutes a critical link mediating aberrant sympathetic drive. Mechanosensitive ion channel Piezo1 and small‑conductance Ca2⁺‑activated K⁺ (SK) channels are abundantly expressed in the PVN. Nevertheless, it remains unclear whether the two channels exert physical protein binding and functional coupling to modulate sympathetic nerve activity. In this study, we applied multiple experimental approaches, including PVN microinjection, neuroelectrophysiological recording, laser‑confocal immunofluorescence staining, and co‑immunoprecipitation (Co‑IP), to explore the interplay between Piezo1 and SK channels and their regulatory effects on sympathetic nerve activity in rats. We found that application of the Piezo1 agonist Yoda1 attenuated the elevation of sympathetic nerve activity and blood pressure evoked by the SK blockers UCL1684 or apamin. Immunofluorescence results revealed that Piezo1 and SK2 co‑localized in PVN pre‑sympathetic neurons that project to the rostral ventrolateral medulla (RVLM). However, no direct physical protein‑protein interactions between them were detected. Our findings demonstrate functional coordination between Piezo1 and SK2 channels in PVN pre‑sympathetic neurons, although direct physical interaction could not be detected in our Co‑IP assays. This synergistic mechanism contributes to homeostatic inhibitory modulation of central sympathetic outflow, and targeting this mechanism may hold potential to alleviate pathological excessive sympathetic overactivity.