Sulfonylurea and K+-Channel Opener Sensitivity of KATP Channels

Koster, Joseph C.; Sha, Qun; Nichols, Colin G.

doi:10.1085/jgp.114.2.203

Cited by 92 publications

(67 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…5). Because the target of pinacidil is SUR (2), this finding supports the finding that PIP 2 modulated the function of SUR1 as well as Kir6.2 (27).…”

Section: Discussionsupporting

confidence: 81%

Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism

Xie

Horie

Takano

1999

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In the COS7 cells transfected with cDNAs of the Kir6.2, SUR2A, and M1 muscarinic receptors, we activated the ATP-sensitive potassium (K ATP) channel with a K ؉ channel opener and recorded the wholecell KATP current. The KATP current was reversibly inhibited by the stimulation of the M 1 receptor, which is linked to phospholipase C (PLC) by the Gq protein. The receptor-mediated inhibition was observed even when protein kinase C (PKC) was inhibited by H-7 or by chelating intracellular Ca 2؉ with 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetate (BAPTA) included in the pipette solution. However, the receptor-mediated inhibition was blocked by U-73122, a PLC inhibitor. M 1-receptor stimulation failed to inhibit the KATP current activated by the injection of exogenous phosphatidylinositol 4,5-bisphosphate (PIP2) through the wholecell patch pipette. The receptor-mediated inhibition became irreversible when the replenishment of PIP2 was blocked by wortmannin (an inhibitor of phosphatidylinositol kinases), or by including adenosine 5-[␤,␥-imido]triphosphate (AMPPNP, a nonhydrolyzable ATP analogue) in the pipette solution. In inside-out patch experiments, the ATP sensitivity of the KATP channel was significantly higher when the M1 receptor in the patch membrane was stimulated by acetylcholine. The stimulatory effect of pinacidil was also attenuated under this condition. We postulate that stimulation of PLC-linked receptors inhibited the KATP channel by increasing the ATP sensitivity, not through PKC activation, but most probably through changing PIP2 levels.T he ATP-sensitive potassium (K ATP ) channels play a key role in the coupling between cellular metabolism and electrical activity in a wide range of tissues. Although the primary characteristic of the K ATP channel is the inhibition by intracellular ATP, various cytosolic substances, such as divalent cations, protons, anions, and nucleoside diphosphates, are known as modulators of the K ATP channel (1-4).In addition to the cytosolic factors listed above, a component of membrane lipid bilayer also modulates the K ATP channel; phosphatidylinositol (PI)-4,5-bisphosphate (PIP 2 ) is known to increase the open probability and decrease the ATP sensitivity of the cardiac and reconstituted K ATP channel (5-8). Membrane PIP 2 content increases when PI and PI 4-monophosphate (PIP) are consecutively phosphorylated by PI 4-kinase and PIP 5-kinase (9). On the other hand, PIP 2 content should decrease when PIP 2 is dephosphorylated by inositolpolyphosphate phosphatase (10) or hydrolyzed by phospholipase C (PLC). In fact, it has been reported that the receptor-mediated activation of PLC decreased PIP 2 content in the plasma membrane of Chinese hamster ovary (CHO) cells and human neuroblastoma cells (11,12).PLC-linked receptors are distributed in many tissues, including cardiac myocytes and pancreatic ␤-cells, where K ATP channels are also present. This raises the question of whether PLC-linked receptors might modulate the K ATP channel by changing PIP 2 levels (8) and ultima...

show abstract

“…5). Because the target of pinacidil is SUR (2), this finding supports the finding that PIP 2 modulated the function of SUR1 as well as Kir6.2 (27).…”

Section: Discussionsupporting

confidence: 81%

Phospholipase C-linked receptors regulate the ATP-sensitive potassium channel by means of phosphatidylinositol 4,5-bisphosphate metabolism

Xie

Horie

Takano

1999

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…To our surprise, mutation Y230A in the proposed B site also prevented tolbutamide from rescuing the trafficking mutants; whereas this may suggest a role of Tyr 230 in tolbutamide binding, an alternative possibility is that the residue is involved in post-binding events that are important for the rescue effect of the drug. In this regard, the cytoplasmic loop where Tyr 230 resides has been proposed to interact with the N terminus of Kir6.2 to control channel activity; deletion of the N terminus of Kir6.2 causes uncoupling between tolbutamide binding in SUR1 and channel activity block (19,28,(45)(46)(47). The Y230A mutation might abolish the tolbutamide rescue effect on the trafficking mutants by disrupting the cross-talk between SUR1 and Kir6.2, which we have shown to be necessary for the sulfonylurea rescue effects.…”

Section: Discussionmentioning

confidence: 99%

Sulfonylureas Correct Trafficking Defects of Disease-causing ATP-sensitive Potassium Channels by Binding to the Channel Complex

Yan

Casey

Shyng

2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

ATP-sensitive potassium (K ATP ) channels mediate glucoseinduced insulin secretion by coupling metabolic signals to ␤-cell membrane potential and the secretory machinery. Reduced K ATP channel expression caused by mutations in the channel proteins: sulfonylurea receptor 1 (SUR1) and Kir6.2, results in loss of channel function as seen in congenital hyperinsulinism. Previously, we reported that sulfonylureas, oral hypoglycemic drugs widely used to treat type II diabetes, correct the endoplasmic reticulum to the plasma membrane trafficking defect caused by two SUR1 mutations, A116P and V187D. In this study, we investigated the mechanism by which sulfonylureas rescue these mutants. We found that glinides, another class of SUR-binding hypoglycemic drugs, also markedly increased surface expression of the trafficking mutants. Attenuating or abolishing the ability of mutant SUR1 to bind sulfonylureas or glinides by the following mutations: Y230A, S1238Y, or both, accordingly diminished the rescuing effects of the drugs. Interestingly, rescue of the trafficking defects requires mutant SUR1 to be co-expressed with Kir6.2, suggesting that the channel complex, rather than SUR1 alone, is the drug target. Observations that sulfonylureas also reverse trafficking defects caused by neonatal diabetes-associated Kir6.2 mutations in a way that is dependent on intact sulfonylurea binding sites in SUR1 further support this notion. Our results provide insight into the mechanistic and structural basis on which sulfonylureas rescue K ATP channel surface expression defects caused by channel mutations.Regulation of insulin secretion by blood glucose relies on expression of functional ATP-sensitive potassium (K ATP ) channels at the ␤-cell membrane. The ␤-cell K ATP channel is an octameric protein complex comprising four pore-forming Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) 2 subunits (1-3). Channel activity is determined by the interplay between both channel subunits and intracellular ATP and ADP: binding of ATP to the Kir6.2 subunit inhibits channel activity, whereas binding of Mg 2ϩ -complexed ATP or ADP to the SUR1 subunit stimulates channel activity (4 -6). In this way, channel activity serves as a reporter of intracellular ATP and ADP concentrations during glucose metabolism to control ␤-cell excitability, hence insulin secretion. Dysfunction of ␤-cell K ATP channels because of mutations in the channel subunits Kir6.2 or SUR1 underlies congenital insulin secretion disorders (4, 5). Whereas mutations causing loss of channel function lead to excessive insulin secretion and hypoglycemia as seen in patients with congenital hyperinsulinism (CHI), those causing gain of channel function lead to insufficient insulin secretion and permanent neonatal diabetes mellitus (PNDM).In congenital hyperinsulinism, two prominent mechanisms accounting for loss of channel function are loss of channel expression at the cell surface and loss of channel sensitivity to stimulation by MgADP (7). In contrast, gain of channel function a...

show abstract

“…Point mutations were made in a Kir6.2⌬C36-C166S construct (Kir6.2⌬CS), in which the C terminus was truncated by 36 amino acids and cysteine 166 was replaced by serine. Mutations were prepared by overlap extension at the junctions of relevant residues using the sequential polymerase chain reaction (16), and the resulting polymerase chain reaction products were subcloned into the pCMV6b vector for transfection. In some experiments, we used a mutant form of SUR1 in which glycine 1485 was replaced by aspartic acid (abbreviated here as SUR1-GD).…”

Section: Methodsmentioning

confidence: 99%