BACKGROUND: Dysfunction of endothelial cells manifests early in pulmonary arterial hypertension and represents a critical therapeutic target. Nevertheless, the limited efficacy of single-target interventions underscores the need for innovative strategies that enable precise therapeutic modulation. METHOD: The TRPV4 (transient receptor potential vanilloid 4)-KCa2.3 (small-conductance calcium-activated potassium channel) interaction was validated in experimental pulmonary hypertension mice using co-immunoprecipitation and fluorescence (Förster) resonance energy transfer. Based on structure-guided molecular docking, a small-molecule candidate, JNc-455, was rationally designed. RESULT: ), indicating that the action of JNc-455 critically depends on the structural integrity of the complex. CONCLUSIONS: This study investigates the critical role of the TRPV4-KCa2.3 complex in pulmonary arterial hypertension and, based on these findings, facilitates drug development and screening, thereby identifying JNc-455 as a promising novel therapeutic candidate for pulmonary arterial hypertension.
Yang et al. (Wed,) studied this question.