ABCC8 and ABCC9: ABC transporters that regulate K+ channels

Bryan, Joseph; Muñoz, Alvaro; Zhang, Xinna; Düfer, Martina; Drews, Gisela; Koehler, Peter; Aguilar‐Bryan, Lydia

doi:10.1007/s00424-006-0116-z

Cited by 145 publications

(115 citation statements)

References 162 publications

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“…SURs are typical ABC transporter proteins due to their topology, and various compounds were demonstrated to modulate their activity as phosphoinositides and long-chain acyl coenzyme A derived from fatty acids. 53 The fact that most of the genes with altered expression due to ABCC6/MRP6 deficiency belong to the ABCA subclass points to a role of ABCC6/MRP6 in lipid metabolism. This assumption is underlined by the identification of ABCC9/SUR2 as further candidate in PXE pathogenesis since ABCC9 is also affected by intermediates of lipid biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Hendig

Langmann

Kocken

et al. 2008

Laboratory Investigation

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Mutations in the ABCC6 gene, encoding the multidrug resistance-associated protein 6 (MRP6), cause pseudoxanthoma elasticum (PXE). This heritable disorder leads to pathological alterations in connective tissues. The implication of MRP6 deficiency in PXE is still unknown. Moreover, nothing is known about a possible compensatory expression of other ATP binding-cassette (ABC) transporter proteins in MRP6-deficient cells. We investigated the gene expression profile of 47 ABC transporters in human dermal fibroblasts of healthy controls (n ¼ 2) and PXE patients (n ¼ 4) by TaqMan low-density array. The analysis revealed the expression of 37 ABC transporter genes in dermal fibroblasts. ABCC6 gene expression was not quantifiable in fibroblasts derived from PXE patients. Seven genes (ABCA6, ABCA9, ABCA10, ABCB5, ABCC2, ABCC9 and ABCD2) were induced, whereas the gene expression of one gene (ABCA3) was decreased, comparing controls and PXE patients (with at least twofold changes). We reanalyzed the gene expression of selected ABC transporters in a larger set of dermal fibroblasts from controls and PXE patients (n ¼ 6, each). Reanalysis showed high interindividual variability between samples, but confirmed the results obtained in the array analysis. The gene expression of ABC transporter genes, as well as lineage markers of PXE, was further examined after inhibition of ABCC6 gene expression by using specific small-interfering RNA. These experiments corroborated the observed gene expression alterations, most notably in the ABCA subclass (up to fourfold, Po0.05). We therefore conclude that MRP6-deficient dermal fibroblasts exhibit a distinct gene expression profile of ABCA transporters, potentially to compensate for MRP6 deficiency. Moreover, our results point to a function for ABCC6/MRP6 in sterol transport, as sterols are preferential regulators of ABCA transporter activity and expression. Further studies are now required to uncover the role of ABCA transporters in PXE.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Hendig

Langmann

Kocken

et al. 2008

Laboratory Investigation

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“…SUR1 is a member of the ATP-binding cassette (ABC) superfamily and is best known for its role in formation of K ATP channels [3][4][5][6][7]. Recently, SUR1 has also come to be recognized for its role in formation of SUR1-regulated NC Ca-ATP channels [8;9].…”

Section: Sulfonylurea Receptor 1 (Sur1)mentioning

confidence: 99%

“…The SUR1-regulated K ATP channel has been extensively reviewed [3][4][5][6][7]. Its potential role in CNS ischemia and trauma will only be briefly mentioned here.…”

Section: Sur1-regulated K Atp Channelmentioning

confidence: 99%

Drugs acting on SUR1 to treat CNS ischemia and trauma

Simard

Woo

Bhatta

et al. 2008

Current Opinion in Pharmacology

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SUMMARYSulfonylurea receptor 1 (SUR1) is a molecule with more diverse and critically important functions than previously recognized. Long viewed simply as a subunit involved in formation of subset of K (ATP) channels, accumulating evidence indicates that SUR1 is newly upregulated in CNS ischemia and injury and is surprisingly promiscuous in its association with different pore-forming subunits, which endow it with new roles not previously envisioned. In this review, we focus on the SUR1-regulated NC(Ca-ATP) channel, its emerging role in CNS ischemia and trauma, and the growing evidence from preclinical and clinical studies demonstrating the potential importance of block of SUR1 by sulfonylureas such as glibenclamide (glyburide) in conditions as seemingly diverse as stroke and spinal cord injury.

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“…The pancreatic K ATP channel comprises Kir6.2 and SUR1 subunits, which are encoded by the genes KCNJ11 and ABCC8, respectively (5,6,10,11). Mutations in both of these genes are associated with disorders of insulin secretion including congenital hyperinsulinism and neonatal diabetes (4,7).…”

mentioning

confidence: 99%

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

Manna¹,

Smith²,

Taneja

et al. 2010

Journal of Biological Chemistry

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Pancreatic ATP-sensitive potassium (K ATP ) channels control insulin secretion by coupling the excitability of the pancreatic ␤-cell to glucose metabolism. Little is currently known about how the plasma membrane density of these channels is regulated. We therefore set out to examine in detail the endocytosis and recycling of these channels and how these processes are regulated. To achieve this goal, we expressed K ATP channels bearing an extracellular hemagglutinin epitope in human embryonic kidney cells and followed their fate along the endocytic pathway. Our results show that K ATP channels undergo multiple rounds of endocytosis and recycling. Further, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly decreases K ATP channel surface density by reducing channel recycling and diverting the channel to lysosomal degradation. These findings were recapitulated in the model pancreatic ␤-cell line INS1e, where activation of PKC leads to a decrease in the surface density of native K ATP channels. Because sorting of internalized channels between lysosomal and recycling pathways could have opposite effects on the excitability of pancreatic ␤-cells, we propose that PKC-regulated K ATP channel trafficking may play a role in the regulation of insulin secretion.The ATP-sensitive potassium (K ATP ) channel plays a key role in the regulation of glucose-induced insulin secretion by the pancreatic ␤-cells (1-3). Central to this role is its unique ability to couple changes in the metabolism of glucose to changes in membrane potential. A rise in blood glucose levels increases the uptake and metabolism of glucose, resulting in an increase in the intracellular [ATP]/[ADP] ratio and inhibition of K ATP channels. This leads to depolarization of the ␤-cell membrane (caused by inhibition of K ϩ efflux), stimulating opening of voltage-activated calcium channels, Ca 2ϩ influx, and insulin release (4). Regulation of K ATP channel function by products of metabolism (e.g. nucleotides) as well as other cellular signals (e.g. protein kinases, lipids) has been extensively studied (1,5,6). By comparison, little is known about how the number of channels at the plasma membrane of the cell is controlled, although there is growing evidence that changes in the membrane density of the channel underlie disease states (7,8).Structurally, K ATP channels exist as octamers formed from four subunits of the inwardly rectifying potassium channel Kir6.1 or Kir6.2, together with four sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits (5, 9 -11). The pancreatic K ATP channel comprises Kir6.2 and SUR1 subunits, which are encoded by the genes KCNJ11 and ABCC8, respectively (5, 6, 10, 11). Mutations in both of these genes are associated with disorders of insulin secretion including congenital hyperinsulinism and neonatal diabetes (4, 7). Studies have shown that although some mutations affect the nucleotide regulation of the channel (12-14), others alter the density of the channels at the cell surface by affecting traffickin...

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ABCC8 and ABCC9: ABC transporters that regulate K+ channels

Cited by 145 publications

References 162 publications

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis

Drugs acting on SUR1 to treat CNS ischemia and trauma

Constitutive Endocytic Recycling and Protein Kinase C-mediated Lysosomal Degradation Control KATP Channel Surface Density

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