Sur1-Trpm4 Cation Channel Expression in Human Cerebral Infarcts

Abstract

In animal models of stroke, spinal cord injury, and subarachnoid hemorrhage, transient receptor potential melastatin 4 (Trpm4), a non-selective monovalent cation channel, is transcriptionally upregulated in neural and vascular cells. In these contexts, Trpm4 has been shown to co-associate with sulfonylurea receptor 1 (Sur1) to form Sur1-Trpm4 channels, which play a critical role in cytotoxic edema, accidental necrotic (oncotic) cell death, blood-brain barrier (BBB) breakdown and formation of vasogenic edema. To date, the expression and molecular interactions of Trpm4 within human cerebral infarcts have not been systematically evaluated. In this study, we examined Trpm4 expression in postmortem specimens obtained from 15 patients within the first 31 days after onset of focal cerebral ischemia. Significant upregulation of Trpm4 protein was found in all cases, relative to controls. De novo transcriptional upregulation of Trpm4 protein was confirmed using in situ hybridization for Trpm4 mRNA. Trpm4 co-localized and co-associated with Sur1 within ischemic endothelial cells and neurons which exhibited membrane thickening and irregularities characteristic of necrotic cell death. Sur1 and Trpm4 co-expression in abnormal endothelial cells also was associated with vasogenic edema, as evidenced by upregulated perivascular TNFα, perivascular extravasation of serum immunoglobulin G and associated inflammation. Upregulated Trpm4 protein persisted up to one month post onset of cerebral ischemia. Furthermore, pharmacological channel blockade by glibenclamide, a selective inhibitor of sulfonylurea receptor, was found to mitigate perivascular TNFα labeling in a rat middle cerebral artery occlusion (MCAo) stroke model. We conclude that the Sur1-Trpm4 channel is upregulated and associated with BBB disruption and cerebral edema formation in human cerebral infarcts. These data suggest that pharmacological targeting of this channel may represent a promising therapeutic strategy for clinical management of ischemic stroke.

SUR1‐TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling

“…Together, the above experiments indicated that AQP4 M1 and M23 co‐associate with the SUR1‐TRPM4 heteromer through physical co‐associations with both TRPM4 and SUR1. Since direct interaction of SUR1 with TRPM4 has been validated in previous reports (Chen et al, ; Woo et al, ; Mehta et al, ), these experiments were not repeated here.…”

“…Normally, astrocytes constitutively express high levels of AQP4 (Nielsen et al, ), but do not express SUR1 or TRPM4 (Chen and Simard, ; Chen et al, ; Mehta et al, ; Simard et al, ). Thus, immunohistochemistry was used to determine if TRPM4 and SUR1 were upregulated in cerebellar astrocytes following cold injury.…”

“…After CNS injury, astrocytes exhibit de novo upregulation of sulfonylurea receptor 1 (SUR1)—transient receptor potential melastatin 4 (TRPM4) channels (Chen and Simard ; Chen et al, ; Mehta et al, ; Simard et al, ). TRPM4, the pore‐forming subunit, is a nonselective monovalent cation channel activated by intracellular calcium ( ) (Vennekens and Nilius, ).…”

“…Furthermore, clinical trials indicate that pharmacological blockade of SUR1‐TRPM4 reduces brain swelling after ischemic stroke (Sheth et al, ). Unlike most other ion channels and transporters implicated in astrocyte swelling, SUR1‐TRPM4 is only expressed after injury (Chen and Simard, ; Chen et al, ; Mehta et al, ; Simard et al, ), when astrocyte swelling predominates. However, the role of SUR1‐TRPM4, if any, in AQP4‐mediated water transport is unknown.…”

Exploratory analysis of oral glibenclamide in acute ischemic stroke

“…27 The hypothesis is further evidenced by the coexpression of Sur1 and Trpm4 in necrotic endothelial cells and neurons in postmortem brain specimens from patients with focal cerebral ischemia, and the upregulated Sur1-Trpm4 channels were associated with blood-brain barrier disruption and cerebral edema. 28 Retrospective studies in diabetics with acute ischemic stroke and used sulfonylurea around the onset have suggested a protective role of sulfonylurea in blood-brain barrier. 12,13 However, the types and dosages of sulfonylurea agents varied in these two studies, leading to inconclusive findings.…”