A touching case of channel regulation: the ATP-sensitive K+ channel

doi:10.1016/S0959-4388(98)80055-X

Current Opinion in Neurobiology

Volume 8, Issue 3, June 1998, Pages 316-320

https://doi.org/10.1016/S0959-4388(98)80055-X Get rights and content

Abstract

The classical type of K_ATP channel is an octameric (4:4) complex of two structurally unrelated subunits, Kir6.2 and SUR. The former serves as an ATP-inhibitable pore, while SUR is a regulatory subunit endowing sensitivity to sulphonylurea and K⁺ channel opener drugs, and the potentiatory action of MgADP. Both subunits are required to form a functional channel.

References (48)

AshcroftFM et al.
Electrophysiology of the pancreatic β-cell
Prog Biophys Mol Biol
(1989)
TusnadyGE et al.
Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters
FEBS Lett
(1997)
SakuraH et al.
Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel expressed in pancreatic β-cells, brain, heart and skeletal muscle
FEBS Lett
(1995)
InagakiN et al.
A family of sulfonylurea receptors determines the properties of ATP-sensitive K⁺ channels
Neuron
(1996)
AdelmanJP
Proteins that interact with the pore-forming subunits of voltage-gated ion channels
Curr Opin Neurobiol
(1995)
InagakiN et al.
Subunit stoichiometry of the pancreatic β-cell ATP-sensitive K⁺ channel
FEBS Lett
(1997)
TrappS et al.
Activation and inhibition of K_ATP currents by guanine nucleotides is mediated by different channel subunits
Proc Natl Acad Sci USA
(1997 vn 94)
SpanswickD et al.
Leptin activates hypothalamic neurons by activation of ATP-sensitive potassium channels
Nature
(1997)
AshcroftFM et al.
Properties and functions of ATP-sensitive K-channels
Cell Signal
(1990)
NicholsCG et al.
Adenosine triphosphate-sensitive potassium channels in the cardiovascular system
Am J Physiol
(1991)

QuayleJM et al.

ATP-sensitive and inwardly-rectifying potassium channels in smooth muscle

Physiol Rev

(1997)

EdwardsG et al.

The pharmacology of ATP-sensitive potassium channels

Annu Rev Pharm Toxicol

(1993)

Aguilar-BryanL et al.

Cloning of the β-cell high-affinity sulphonylurea receptor: a regulator of insulin secretion

Science

(1995)

HigginsC

ABC transporter: from microorganisms to man

Annu Rev Cell Biol

(1992)

InagakiN et al.

Reconstitution of I_KATP: an inward rectifier subunit plus the sulphonylurea receptor

Science

(1995)

GribbleFM et al.

Properties of cloned ATP-sensitive K-currents expresed in Xenopus oocytes

J Physiol

(1997)

ChutkowWA et al.

Cloning, tissue expression,and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular K_ATP channels

Diabetes

(1996)

IsomotoS et al.

A novel sulphonylurea receptor forms with BIR (Kir6.2) a smooth muscle type of ATP-sensitive K⁺ channel

J Biol Chem

(1996)

LissB et al.

Single cell RT-PCR detection of ATP-sensitive potassium channel subunits: a heterogeneous expression pattern in dopaminergic neurons

Pflügers Arch

(1997)

KarschinC et al.

Overlapping tissue distribution of K_ATP channel-forming Kir6.2 subunit and the sulphonylurea receptor SUR1 in rodent brain

FEBS Lett

(1996)

AshfordMLJ et al.

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K⁺ channels

Pflügers Arch

(1990)

AshfordMLJ et al.

Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K⁺ channels

Br J Pharmacol

(1990)

YamadaYM et al.

Sulphonylurea receptor SUR2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K⁺ channel

J Physiol

(1997)

ÄmmäläC et al.

The sulphonylurea receptor confers diazoxide sensitivity on the inwardly-rectifyng K-channel, Kir6.1.

J Physiol

(1996)

Cited by (42)

ATP sensitive potassium channel openers: A new class of ocular hypotensive agents
2017, Experimental Eye Research
Citation Excerpt :
SUR2A and SUR2B are identical except for the terminal 42 amino acid residues (Fig. 1B). ( Aguilar-Bryan et al., 1998) Both SUR1 and SUR2 are members of the ATP binding cassette (ABC) transporter superfamily, a common membrane protein found in all species that use energy from ATP hydrolysis to selectively translocate specific molecules across the cell membrane (Higgins and Linton, 2001; Tucker and Ashcroft, 1998). Similar to other ABC proteins, the SUR subunits contain two nuclear binding domains and two consensus nucleotide binding motifs (Conti et al., 2001).
ATP sensitive potassium (K_ATP) channels connect the metabolic and energetic state of cells due to their sensitivity to ATP and ADP concentrations. K_ATP channels have been identified in multiple tissues and organs of the body including heart, pancreas, vascular smooth muscles and skeletal muscles. These channels are obligatory hetero-octamers and contain four sulfonylurea (SUR) and four potassium inward rectifier (K_ir) subunits. Based on the particular type of SUR and K_ir present, there are several tissue specific subtypes of K_ATP channels, each with their own unique set of functions. Recently, K_ATP channels have been reported in human and mouse ocular tissues. In ex vivo and in vivo model systems, K_ATP channel openers showed significant ocular hypotensive properties with no appearance of toxic side effects. Additionally, when used in conjunction with known intraocular pressure lowering drugs, an additive effect on IOP reduction was observed. These K_ATP channel openers have also been reported to protect the retinal ganglion cells during ischemic stress and glutamate induced toxicity suggesting a neuroprotective property for this drug class. Medications that are currently used for treating ocular hypertensive diseases like glaucoma do not directly protect the affected retinal cells, are sometimes ineffective and may show significant side effects. In light of this, K_ATP channel openers with both ocular hypotensive and neuroprotective properties, have the potential to develop into a new class of glaucoma therapeutics.
Oleate induces K<inf>ATP</inf> channel-dependent hyperpolarization in mouse hypothalamic glucose-excited neurons without altering cellular energy charge
2017, Neuroscience
Citation Excerpt :
Previously it has been suggested that oleate may inhibit ATP-dependent gating of an acetylcholine-modulated potassium channel (Kim and Pleumsamran, 2000). As KATP channel activity is controlled to a large extent by the ATP/ADP ratio in cells, with ATP-inhibiting and ADP-activating KATP activity, respectively (Tucker and Ashcroft, 1998), a simple explanation for the oleate-mediated hyperpolarization could be reduced ATP-dependent inhibition of channel activity. To examine this possibility, we first decided to replace ATP with the non-hydrolyzable ATP analog, 5′-adenylylimidodiphosphate (AMP-PNP; 3 mM) in the pipette solution.
The unsaturated fatty acid, oleate exhibits anorexigenic properties reducing food intake and hepatic glucose output. However, its mechanism of action in the hypothalamus has not been fully determined. This study investigated the effects of oleate and glucose on GT1-7 mouse hypothalamic cells (a model of glucose-excited (GE) neurons) and mouse arcuate nucleus (ARC) neurons. Whole-cell and perforated patch-clamp recordings, immunoblotting and cell energy status measures were used to investigate oleate- and glucose-sensing properties of mouse hypothalamic neurons. Oleate or lowered glucose concentration caused hyperpolarization and inhibition of firing of GT1-7 cells by the activation of ATP-sensitive K⁺ channels (K_ATP). This effect of oleate was not dependent on fatty acid oxidation or raised AMP-activated protein kinase activity or prevented by the presence of the UCP2 inhibitor genipin. Oleate did not alter intracellular calcium, indicating that CD36/fatty acid translocase may not play a role. However, oleate activation of K_ATP may require ATP metabolism. The short-chain fatty acid octanoate was unable to replicate the actions of oleate on GT1-7 cells. Although oleate decreased GT1-7 cell mitochondrial membrane potential there was no change in total cellular ATP or ATP/ADP ratios. Perforated patch and whole-cell recordings from mouse hypothalamic slices demonstrated that oleate hyperpolarized a subpopulation of ARC GE neurons by K_ATP activation. Additionally, in a separate small population of ARC neurons, oleate application or lowered glucose concentration caused membrane depolarization. In conclusion, oleate induces K_ATP-dependent hyperpolarization and inhibition of firing of a subgroup of GE hypothalamic neurons without altering cellular energy charge.
Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel
2010, European Journal of Pharmacology
The biguanides, phenformin and metformin, are used in the treatment of type II diabetes mellitus, as well as being routinely used in studies investigating AMPK activity. We used the patch-clamp technique and rubidium flux assays to determine the role of these drugs in ATP-sensitive K⁺ channel (K_ATP) regulation in cell lines expressing the cloned components of K_ATP and the current natively expressed in vascular smooth muscle cells (VSMCs). Phenformin but not metformin inhibits a number of variants of K_ATP including the cloned equivalents of currents present in vascular and non-vascular smooth muscle (Kir6.1/SUR2B and Kir6.2/SUR2B) and pancreatic β-cells (Kir6.2/SUR1). However it does not inhibit the current potentially present in cardiac myocytes (Kir6.2/SUR2A). The highest affinity interaction is seen with Kir6.1/SUR2B (IC₅₀ = 0.55 mM) and it also inhibits the current in native vascular smooth muscle cells. The extent and rate of inhibition are similar to that seen with the known K_ATP blocker PNU 37883A. Additionally, phenformin inhibited the current elicited through the Kir6.2ΔC26 (functional without SUR) channel with an IC₅₀ of 1.78 mM. Phenformin reduced the open probability of Kir6.1/SUR2B channels by ∼ 90% in inside-out patches. These findings suggest that phenformin interacts directly with the pore-forming Kir6.0 subunit however the sulphonylurea receptor is able to significantly modulate the affinity. It is likely to block from the intracellular side of the channel in a manner analogous to that of PNU 37883A.
Stevioside and related compounds: Therapeutic benefits beyond sweetness
2009, Pharmacology and Therapeutics
Stevioside, an abundant component of Stevia rebaudiana leaf, has become well-known for its intense sweetness (250–300 times sweeter than sucrose) and is used as a non-caloric sweetener in several countries. A number of studies have suggested that, beside sweetness, stevioside along with related compounds, which include rebaudioside A (second most abundant component of S. rebaudiana leaf), steviol and isosteviol (metabolic components of stevioside) may also offer therapeutic benefits, as they have anti-hyperglycemic, anti-hypertensive, anti-inflammatory, anti-tumor, anti-diarrheal, diuretic, and immunomodulatory actions. It is of interest to note that their effects on plasma glucose level and blood pressure are only observed when these parameters are higher than normal. As steviol can interact with drug transporters, its role as a drug modulator is proposed. This review summarizes the current knowledge of the pharmacological actions, therapeutic applications, pharmacokinetics and safety of stevioside and related compounds. Although much progress has been made concerning their biological and pharmacological effects, questions regarding chemical purity and safety remain unsolved. These issues are discussed to help guide future research directions.
ATP regulation of a large conductance voltage-gated cation channel in rough endoplasmic reticulum of rat hepatocytes
2008, Archives of Biochemistry and Biophysics
ATP-sensitive K⁺ channels play an important role in regulating membrane potential during metabolic stress. In this work we report the effect of ATP and ADP-Mg on a K⁺ channel present in the membrane of rough endoplasmic reticulum (RER) from rat hepatocytes incorporated into lipid bilayers. Channel activity was found to decrease in presence of ATP 100 μM on the cytoplasmic side and was totaly inhibited at ATP concentrations greater than 0.25 mM. The effect appeared voltage dependent, suggesting that the ATP binding site was becoming available upon channel opening. Channel activity was suppressed by the nonhydrolyzable ATP analog (ATPγS), ruling out a phosphorylation-based mechanism. Notably addition of 2.5 mM ADP-Mg to the cytosolic side increased the channel open probability at negative potentials. We conclude that the large conductance voltage-gated cation channel in RER of rat hepatocytes is an ATP and ADP sensitive channel likely to be involved in cellular processes such as Ca²⁺ signaling or control of membrane potential across the endoplasmic reticulum membrane.
Kir
2007, xPharm: The Comprehensive Pharmacology Reference

View all citing articles on Scopus

View full text

A touching case of channel regulation: the ATP-sensitive K+ channel

Abstract

Prog Biophys Mol Biol

FEBS Lett

FEBS Lett

Neuron

Curr Opin Neurobiol

FEBS Lett

Proc Natl Acad Sci USA

Nature

Properties and functions of ATP-sensitive K-channels

Cell Signal

Adenosine triphosphate-sensitive potassium channels in the cardiovascular system

Am J Physiol

ATP-sensitive and inwardly-rectifying potassium channels in smooth muscle

Physiol Rev

The pharmacology of ATP-sensitive potassium channels

Annu Rev Pharm Toxicol

Cloning of the β-cell high-affinity sulphonylurea receptor: a regulator of insulin secretion

Science

ABC transporter: from microorganisms to man

Annu Rev Cell Biol

Reconstitution of IKATP: an inward rectifier subunit plus the sulphonylurea receptor

Science

Properties of cloned ATP-sensitive K-currents expresed in Xenopus oocytes

J Physiol

Cloning, tissue expression,and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels

Diabetes

A novel sulphonylurea receptor forms with BIR (Kir6.2) a smooth muscle type of ATP-sensitive K+ channel

J Biol Chem

Single cell RT-PCR detection of ATP-sensitive potassium channel subunits: a heterogeneous expression pattern in dopaminergic neurons

Pflügers Arch

Overlapping tissue distribution of KATP channel-forming Kir6.2 subunit and the sulphonylurea receptor SUR1 in rodent brain

FEBS Lett

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels

Pflügers Arch

Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels

Br J Pharmacol

Sulphonylurea receptor SUR2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel

J Physiol

The sulphonylurea receptor confers diazoxide sensitivity on the inwardly-rectifyng K-channel, Kir6.1.

J Physiol

A touching case of channel regulation: the ATP-sensitive K⁺ channel

Reconstitution of I_KATP: an inward rectifier subunit plus the sulphonylurea receptor

Cloning, tissue expression,and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular K_ATP channels

A novel sulphonylurea receptor forms with BIR (Kir6.2) a smooth muscle type of ATP-sensitive K⁺ channel

Overlapping tissue distribution of K_ATP channel-forming Kir6.2 subunit and the sulphonylurea receptor SUR1 in rodent brain

Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K⁺ channels

Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K⁺ channels

Sulphonylurea receptor SUR2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K⁺ channel