Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion

Abstract

In severe traumatic brain injury (TBI), contusions often are worsened by contusion expansion or hemorrhagic progression of contusion (HPC), which may double the original contusion volume and worsen outcome. In humans and rodents with contusion-TBI, sulfonylurea receptor 1 (SUR1) is upregulated in microvessels and astrocytes, and in rodent models, blockade of SUR1 with glibenclamide reduces HPC. SUR1 does not function by itself, but must co-assemble with either KIR6.2 or transient receptor potential cation channel subfamily M member 4 (TRPM4) to form K (SUR1-KIR6.2) or SUR1-TRPM4 channels, with the two having opposite effects on membrane potential. Both KIR6.2 and TRPM4 are reportedly upregulated in TBI, especially in astrocytes, but the identity and function of SUR1-regulated channels post-TBI is unknown. Here, we analyzed human and rat brain tissues after contusion-TBI to characterize SUR1, TRPM4, and KIR6.2 expression, and in the rat model, to examine the effects on HPC of inhibiting expression of the three subunits using intravenous antisense oligodeoxynucleotides (AS-ODN). Glial fibrillary acidic protein (GFAP) immunoreactivity was used to operationally define core versus penumbral tissues. In humans and rats, GFAP-negative core tissues contained microvessels that expressed SUR1 and TRPM4, whereas GFAP-positive penumbral tissues contained astrocytes that expressed all three subunits. Förster resonance energy transfer imaging demonstrated SUR1-TRPM4 heteromers in endothelium, and SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. In rats, glibenclamide as well as AS-ODN targeting SUR1 and TRPM4, but not KIR6.2, reduced HPC at 24 h post-TBI. Our findings demonstrate upregulation of SUR1-TRPM4 and K after contusion-TBI, identify SUR1-TRPM4 as the primary molecular mechanism that accounts for HPC, and indicate that SUR1-TRPM4 is a crucial target of glibenclamide.

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…Patterns of increased SUR1±TRPM4 expression in post-traumatic human contusions are similar to those described in rat TBI models (Table 1) [50,51,[60][61][62]. Scientific research understanding the complexity of SUR1's association with its pore-forming subunit partners in TBI is limited, but rapidly evolving.…”

“…SUR1-KIR6.2 mediates potassium efflux and hyperpolarizes cells; channel blockade by GLI stimulates insulin release, thus leading to its utility in the treatment of diabetes mellitus [46][47][48][49]. Of note, SUR1-KIR6.2 is also expressed in the CNS, including after TBI [50,51].…”

“…Unlike many other constitutively expressed SUR1 regulated channels in various systemic tissues, SUR1-TRPM4 is unique in that it is not normally present in the CNS, but undergoes de novo upregulation after CNS injury [36]. Upregulation of SUR1 with or without TRPM4 (hereafter SUR1±TRPM4) has been demonstrated in multiple CNS cell types (neurons, astrocytes, endothelial cells, macrophages, microglia) and models of injury, including ischemic stroke [56][57][58][59], TBI [50,[60][61][62], spinal cord injury (SCI) [63,64], intracerebral hemorrhage (ICH) [65], subarachnoid hemorrhage (SAH) [66,67], CNS metastases [68], cardiac arrest [69,70], hepatic failure [71], and encephalomyelitis [72][73][74] ( Figure 1A). The increased expression in several cell-types of the neurovascular unit renders SUR1-TRPM4 a likely contributor across the spectrum of cerebral edema endotypes (reviewed elsewhere [14,15,75]), including cellular/cytotoxic edema, ionic edema, vasogenic edema, and eventually hemorrhagic transformation/progression with complete disintegration of the BBB and oncotic death of endothelial cells ( Figure 1C) [14,15,76].…”

“…This is associated with cellular edema, blebbing and oncotic cell death. Individual images adapted with permission from Chen et al, 2001, Martinez-Valverde et al, 2015, Gerzanich et al, 2019 This is a proposed model of a SUR1-TRPM4-AQP4 hetero-multimeric complex showing AQP4 tetramers (blue channels) interposed within the SUR1-TRPM4 octamer (top view on the left, coronal view on the right). This model demonstrates SUR1-TRPM4 activation by increased intracellular Ca 2+ (green arrow), which results in depolarization from Na + influx and raised intracellular oncotic pressure.…”

“…This will also impact their potential utility as biomarkers. In 2019, Gerzanich et al evaluated SUR1, TRPM4, and KIR6.2 protein expression patterns in human contusion as well as rodent models of TBI; their findings are discussed in detail below (summarized in Table 1) [50]. Based on current information from these studies, SUR1-TRPM4 and SUR1-KIR6.2 multimers are not always expressed together after TBI, however simultaneous expression of SUR1, TRPM4, and KIR6.2 have been reported within certain cell-types [50].…”