Reactome | KCNJ11 tetramer:ABCC8 tetramer binds 4xATP, closing the channel

KCNJ11 tetramer:ABCC8 tetramer binds 4xATP, closing the channel

Stable Identifier

R-HSA-265682

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol, plasma membrane

Synonyms

Closing of Inward Rectifying, ATP-sensitive Potassium Channels (KATP channels)

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

KCNJ11 tetramer:ABCC8 tetramer binds 4xATP, closing the channel

Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

The beta-cell ATP-sensitive potassium channel (KATP channel) comprise the tetrameric ATP-sensitive inward rectifier potassium channel 11 (KCNJ11, Kir6.2) and the tetrameric channel regulator ATP-binding cassette sub-family C member 8 (ABCC8). When the ATP/ADP ratio is high, the KCNJ11 (Kir6.2) subunit binds ATP and the channel closes. Conversely, when the ADP:ATP ratio is high, the ABCC8 (SUR1) subunit binds magnesium-ADP and the channel is open.
The KATP channels in the beta cell are inwardly rectifying (allowing potassium ions to pass out of the cell) and are partially responsible for maintaining the resting potential of the cell, about -70 mV. Closure of the KATP channels causes a depolarization (a reduction in the voltage differential) across the plasma membrane.
The antidiabetic activity of sulfonylurea drugs such as acetohexamide, tolbutamide, glipzide, glibenclamide, and glimepiride is due to their binding ABCC8 (SUR1) subunits and inhibiting potassium efflux. Activated PKA promotes the closing of inward rectifying potassium channels thus leading to depolarization of the plasma membrane of the beta cell and, via opening of voltage-gated calcium channels, causing exocytosis of insulin granules. PKA presumably acts by phosphorylating the potassium channel, but this is not certain. Epac1 is activated by binding cAMP, forms a complex with inward rectifying ATP-sensitive potassium channels, and acts to inhibit (close) the channels. Epac2 is activated by binding cAMP, forms a complex with inward rectifying ATP-sensitive potassium channels, ands acts to inhibit (close) the channels.

Literature References

PubMed ID	Title	Journal	Year
10194514	The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells Miki, T, Nagashima, K, Seino, S	J Mol Endocrinol	1999
20086079	Inwardly rectifying potassium channels: their structure, function, and physiological roles Hibino, H, Inanobe, A, Furutani, K, Murakami, S, Findlay, I, Kurachi, Y	Physiol Rev	2010
17380317	Low levels of glucose transporters and K+ATP channels in human pancreatic beta cells early in development Richardson, CC, Hussain, K, Jones, PM, Persaud, S, Löbner, K, Boehm, A, Clark, A, Christie, MR	Diabetologia	2007
10866047	Sulfonylurea receptor 1 and Kir6.2 expression in the novel human insulin-secreting cell line NES2Y MacFarlane, WM, O'Brien, RE, Barnes, PD, Shepherd, RM, Cosgrove, KE, Lindley, KJ, Aynsley-Green, A, James, RF, Docherty, K, Dunne, MJ	Diabetes	2000
16513675	Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A- and B-cells Vignali, S, Leiss, V, Karl, R, Hofmann, F, Welling, A	J Physiol	2006
17021801	Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes Girard, CA, Shimomura, K, Proks, P, Absalom, N, Castano, L, Perez de Nanclares, G, Ashcroft, FM	Pflugers Arch	2006
10868950	Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice Seino, S, Iwanaga, T, Nagashima, K, Miki, T	Diabetes	2000
11078440	Triggering and amplifying pathways of regulation of insulin secretion by glucose Henquin, JC	Diabetes	2000
17919183	Action potentials and insulin secretion: new insights into the role of Kv channels Jacobson, DA, Philipson, LH	Diabetes Obes Metab	2007
18596924	Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations Pinney, SE, MacMullen, C, Becker, S, Lin, YW, Hanna, C, Thornton, P, Ganguly, A, Shyng, SL, Stanley, CA	J Clin Invest	2008
10206966	Two regions of sulfonylurea receptor specify the spontaneous bursting and ATP inhibition of KATP channel isoforms Babenko, AP, Gonzalez, G, Bryan, J	J Biol Chem	1999
19587354	Coexpression of the type 2 diabetes susceptibility gene variants KCNJ11 E23K and ABCC8 S1369A alter the ATP and sulfonylurea sensitivities of the ATP-sensitive K(+) channel Hamming, KS, Soliman, D, Matemisz, LC, Niazi, O, Lang, Y, Gloyn, AL, Light, PE	Diabetes	2009
16556766	Minireview: implication of mitochondria in insulin secretion and action Wiederkehr, A, Wollheim, CB	Endocrinology	2006
18346985	A rare mutation in ABCC8/SUR1 leading to altered ATP-sensitive K+ channel activity and beta-cell glucose sensing is associated with type 2 diabetes in adults Tarasov, AI, Nicolson, TJ, Riveline, JP, Taneja, TK, Baldwin, SA, Baldwin, JM, Charpentier, G, Gautier, JF, Froguel, P, Vaxillaire, M, Rutter, GA	Diabetes	2008
16332676	A novel KCNJ11 mutation associated with congenital hyperinsulinism reduces the intrinsic open probability of beta-cell ATP-sensitive potassium channels Lin, YW, MacMullen, C, Ganguly, A, Stanley, CA, Shyng, SL	J Biol Chem	2006