Noncanonical ion channel signaling in neurovascular barrier regulation and immune cell trafficking

Ion channels are classically regarded as regulators of electrical excitability, but their role in immune activation and barrier homeostasis extends far beyond global transmembrane ion flux. This functional diversity is, among other things, the result of noncanonical signaling pathways. In this review, we examine the neurovascular endothelium as a paradigm for barrier-associated neuroimmune pathology and discuss three mechanistic principles: (1) permeation-independent scaffolding via cytoplasmic interaction domains, (2) spatio-temporally restricted ion flux within signaling microdomains, and (3) compartmentalized or cargo-mediated signaling. These mechanisms shape endothelial barrier integrity, inflammatory junctional remodeling, and the diapedesis of immune cells across the blood-brain barrier. A deeper understanding of such noncanonical channel functions opens new therapeutic perspectives beyond conventional pore blockade, including the targeted modulation of signaling domains, protein interactions, and subcellular channel localization.