ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target

Abstract

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“KATP”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The KATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is a result of ABCC9 mutations; we discuss neurologic manifestations of this genetic syndrome. More common brain disorders linked to ABCC9 gene variants include hippocampal sclerosis of aging (HS-Aging), sleep disorders, and depression. HS-Aging is a prevalent neurological disease with pathologic features of both neurodegenerative (aberrant TDP-43) and cerebrovascular (arteriolosclerosis) disease. As to potential therapeutic intervention, the human pharmacopeia features both SUR2 agonists and antagonists, so ABCC9/SUR2 may provide a “druggable target”, relevant perhaps to both HS-Aging and Alzheimer’s disease. We conclude that more work is required to better understand the roles of ABCC9/SUR2 in the human brain during health and disease conditions.

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

“…This discrepancy in DZ sensitivities was well explained later by the data of Liu et al, who showed different sensitivity of SUR1 and SUR2 isoforms to DZ and established EC 50 for DZ activation of Kir6.1/SUR1 comprising channel expressed in HEK293 cells to be of the order of 10 µM, which resembled the so-called "mK ATP channel" [4]. Much later studies found the expression of Kir6.1/SUR1 channel in liver mitochondria [35], which was consistent with high sensitivity of liver mK ATP channel to DZ observed experimentally [7]. Meanwhile, in ventricle myocyte mitochondria predominant expression of "DZinsensitive" Kir6.2/SUR2A was established [32,40], although heart and liver mitochondria were shown to not much differ in their sensitivities to DZ [7].…”

“…So, SUR1 comprising channels were shown to be expressed in cardiac tissues [32,33], pancreatic beta cells (Kir6.2/SUR1 [4,10]), liver and liver mitochondria (Kir6.1/SUR1 [34]). SUR2A showed relatively high expression in cardiac and skeletal muscle cells [24,[32][33][34], whereas SUR2B was more broadly expressed in smooth muscle cells and brain [35,36]. In cardiac tissues SUR and Kir subunit distribution showed cell-specificity.…”

“…Thus, molecular entity of Kir subunits of mK ATP channels, even in the best studied heart mitochondria, largely remains unknown. The studies are still more complicated because of the absence of antibodies quite specific for Kir proteins [43] and possible expression of several splice variants of K ATP channel with different biophysical properties [35][36][37][38].…”

Os fatores genéticos da insônia - Uma revisão de literatura

“…O KATP representa um sensor metabólito ao estresse e à hipóxia, auxilia na regulação da unidade neurovascular (NELSON et al, 2015). Logo, o gene ABCC9 e o seu componente polipeptídico, SUR2, ocupam uma posição intrigante para a vasorregulação no cérebro.…”

“…Contudo, valiosos estudos experimentais apontam algumas funções para esses canais como atividades relacionadas ao desenvolvimento e ao metabolismo celular. Isso corrobora para a relação entre o canal KATP e o gene ABCC9 no distúrbio da insônia (NELSON et al, 2015).…”