SUR1-TRPM4 Regulates Aquaporin-4 Subcellular Localization by Astrocytic Endfeet Calcium Signals Following Status Epilepticus.

Abstract

Status epilepticus (SE) is a severe condition that results in uncontrollable cerebral edema and cognitive dysfunction. Recent studies suggest that the localization of aquaporin-4 (AQP4) in astrocytic endfeet plays a crucial role in regulating blood-brain water transport and cell volume control, particularly along perivascular pathways. However, the signaling mechanisms underlying AQP4 localization remain poorly understood. In this study, we utilized the genetically encoded fluorescent calcium (Ca²⁺) indicator GCaMp6f to investigate Ca²⁺ signals in astrocytic somata, processes, and endfeet during SE induction and observed enhanced Ca²⁺ signals in both the somata and perivascular endfeet of astrocytes. We employed genetic knockout of TRPM4 (Trpm4 ^-/- ) and glibenclamide treatment to explore the role of sulfonylurea receptor 1 transient receptor potential melastatin-4 (SUR1-TRPM4) channel in these Ca²⁺ responses. Both approaches significantly suppressed the Ca²⁺ signals in the astrocytic endfeet and reduced perivascular expression of the Ca²⁺-related signaling pathway sensor calmodulin (CaM). Furthermore, we found that AQP4 localization was no longer confined to the domains of astrocytic endfeet following SE. Inhibition of SUR1-TRPM4 through pharmacological blockade or gene deletion restored the subcellular localization of AQP4, reduced cerebral edema, and improved cognitive outcomes post-SE. Our findings suggest that SUR1-TRPM4 plays a pivotal role in regulating astrocytic Ca²⁺ signals and mediating the aberrant expression and subcellular localization of astrocytic AQP4 along perivascular pathways. Together, these findings demonstrate a novel molecular mechanism underscoring SUR1-TRPM4 therapy in the treatment of SE characterized by dysregulated Ca²⁺ signaling in astrocytic endfeet.