Nav1.2 is a homeostatic sleep effector governing sleep quality
Abstract
Sleep is an evolutionarily conserved behavioral state critical for brain function and organismal health, with hundreds of genes linked to sleep regulation identified. However, the comprehensive molecular landscape of sleep, evolutionarily conserved functional processes, and therapeutically targetable signaling modules remain elusive. Here, we address these gaps via a multi-layered approach, constructing a quantitative sleep-regulatory network by integrating data from 217 mouse EEG/EMG-based studies, 156 Drosophila studies, and 25 phosphoproteomic datasets (10 sleep-related, 15 non-sleep). This analysis defines 115 sleep-regulatory genes (S-RGs), 293 sleep-associated phosphoproteins (S-PProts, including 16 S-RGs) and 479 well-annotated site-kinase pairs, while defining their hierarchical functional architecture and identifying neurotransmission, synaptic plasticity, and neuronal excitability as core processes governing sleep homeostasis. Notably, we reveal the unrecognized AKAP7α-RIIβ-PKA-Cα-Nav1.2 complex forms a compact homeostatic module: Nav1.2 undergoes time-dependent cumulative multisite phosphorylation that acts as a molecular timer encoding sleep pressure dynamics, whose slow inactivation gating kinetics directly fine-tuning neuronal excitability and thereby regulate NREMS slow-wave activity (SWA), the gold standard biomarker of sleep quality across multiple mouse models. We further establish direct translational potential: the FDA-approved drug gabapentin specifically enhances sleep quality by promoting Nav1.2 slow inactivation, validating this module as a highly specific, mechanism-based therapeutic target for sleep quality disorders.
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