Physiology and pathophysiology of KATP channels in the pancreas

and cardiovascular system

A review

Susumu Seino*

Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-Ku, Chiba 260-8670, Japan

Received 14 November 2002; accepted 18 November 2002

Abstract

KATP channels are present in pancreatic and extrapancreatic tissues such as heart and smooth muscle, and display diverse molecular

composition. They contain two different structural subunits: an inwardly rectifying potassium channel subunit (Kir6.x) and a sulfonylurea

receptor (SURX). Recent studies on genetically engineered Kir6.2 knockout mice have provided a better understanding of the physiological

and pathophysiological roles of Kir6.2-containing KATP channels. Kir6.2/SUR1 has a pivotal role in pancreatic insulin secretion. Kir6.2/

SUR2A mediates the effects of KATP channels openers on cardiac excitability and contractility and contributes to ischemic preconditioning.

However, controversy remains on the physiological properties of the KATP channels in vascular smooth muscle cells. Kir6.1 knockout mice

exhibit sudden cardiac death due to cardiac ischemia, indicating that Kir6.1 rather than Kir6.2 is critical in the regulation of vascular tone.

This article summarizes current understanding of the physiology and pathophysiology of Kir6.1- and Kir6.2-containing KATP channels.

D 2003 Elsevier Science Inc. All rights reserved.

Keywords: ATP; Sulfonylurea; Inward rectifier

1. Introduction

Adenosine triphosphate (ATP)-sensitive K + channels

are found in a variety of tissues, including pancreatic

b-cells, central neurons, as well as cardiac, smooth, and

skeletal muscle (Ashcroft & Gribble, 1999; Ashford,

Sturgess, Trout, Gardner, & Hales, 1988; Davis, Standen,

& Stanfield, 1991; Nichols & Lederer, 1991; Quayle,

Nelson, & Standen, 1997). They regulate many cellular

functions by coupling the metabolic state of the cell to

its electrophysiological membrane potential (Ashcroft,

1988). As a result of recent progress in molecular

biology and electrophysiology, KATP channel structure

and diversity is increasingly being understood. Cloning,

sequencing, and functional analyses of KATP channel

genes reveal different molecular composition of the

various KATP channels (Seino, 1999). It is now well

known that plasma membrane KATP channels consist of

two different structural subunits: an inwardly rectifying

potassium channel subunit, which forms the pore (Kir6.x),

and a sulfonylurea receptor (SURX) as the regulatory

subunit (Aguilar-Bryan et al., 1998). The subunits

assemble as a hetero-octamer with 4:4 stoichiometry

(Inagaki et al., 1995). Based on sequence similarity,

inwardly rectifying K + channels (Kir6.x) are divided

into seven subfamilies, including Kir6.1 and Kir6.2

(Inagaki et al., 1995). The regulatory sulfonylurea recep-

tor (SUR) subunit is encoded by two different genes,

SUR1 and SUR2. SUR2A and SUR2B are splice var-

iants of SUR2 (Inagaki et al., 1996; Isomoto et al.,

1996). It has been shown that pancreatic b-cell KATP

channels consist of SUR1 and Kir6.2, whereas KATP

channels in cardiomyocytes and skeletal muscle comprise

SUR2A and Kir6.2 (Seino, Iwanaga, Nagashima, &

Miki, 2000) (see Fig. 1). In contrast, vascular and

nonvascular smooth muscle KATP channels are formed

by a coupling of the SUR2B subunit with either Kir6.2

or Kir6.1 (Yamada et al., 1997). KATP channels can be

nonselectively blocked in nonpancreatic tissues by some

sulfonylureas, like glibenclamide, and activated by K +

1056-8727/03/$ – see front matter D 2003 Elsevier Science Inc. All rights reserved.

PII: S1056 -8727 (02 )00274 -X

* Tel.: +81-43-226-2187; fax: +81-43-221-7803.

E-mail address: seino@med.m.chiba-u.ac.jp (S. Seino).

Journal of Diabetes and Its Complications 17 (2003) 2–5

channel-opening drugs such as pinacidil, nicorandil, and

diazoxide (Ashcroft & Gribble, 2000; Beech, Zhang,

Nakao, & Bolton, 1993).

2. Diverse roles of KATP channels

Much insight into the physiological and pathophysio-

logical roles of KATP channels in various tissues has been

gained from genetically engineered mice. A mouse model

expressing a dominant negative form of Kir6.2 in the

pancreatic b-cells and a mouse model lacking Kir6.2

(Kir6.2 knockout mice) (Miki et al., 1998) allow direct

determination of the physiological roles of the KATP

channels in the pancreas (Seino et al., 2000). It has been

shown that Kir6.2/SUR1 channels are critical in both

glucose- and sulfonylurea-induced insulin secretion and

that they play a crucial role in b-cell survival and islet-

cell architecture. In order to clarify the functional role of

the Kir6.2 subunit in cardiac and vascular tissue, Suzuki

et al. (2001) further studied mice generated by knockout

(KO) of the Kir6.2 gene. The effects of pharmacological

K + -channel openers (pinacidil and diazoxide) on cardiac

and vascular smooth muscle KATP channels were deter-

mined in these mice. The results show that Kir6.2/SUR2A

is essential for mediating the depression of cardiac

excitation and contraction induced by K + -channel open-

ers. In contrast, no effect on vasodilation was observed in

response to K + -channel openers, indicating that Kir6.2

plays no discernable role in the artery.

3. Kir6.1-containing potassium channels:

current understanding

The electrophysiological and pharmacological prop-

erties of Kir6.2-containing K + channels have been char-

acterized in detail in reconstitution studies (Inagaki et al.,

1995, 1996) and native tissues (Suzuki et al., 2001,

2002). However, the physiological role of Kir6.1-contain-

ing KATP channels is poorly understood. Yamada et al.

(1997) showed that coexpression of Kir6.1 and SUR2B

produces a K + current that is activated by nucleoside

diphosphates such as uridine diphosphate (UDP) and

inhibited by the sulfonylurea glibenclamide. These prop-

erties were found to be similar to those observed for

ATP-sensitive K + channels in vascular smooth muscle

(Beech et al., 1993; Standen et al., 1989). However, it

remained to be shown whether Kir6.1 was an essential

component of KATP channels.

4. Kir6.1-containing potassium channels:

recent advances

To further clarify the physiological role of Kir6.1-con-

taining channels, mice lacking the gene encoding Kir6.1

(Kcnj8) were generated (Miki et al., 2002). Surprisingly,

these mice exhibited a high rate of sudden cardiac death

between 30 and 40 days after birth.

On the electrocardiogram, spontaneous ST-segment

elevation followed by a series of severe atrioventricular

(AV) blocks were documented in these cases, whereas no

such abnormality was recorded in Kir6.2 knockout mice.

Sudden cardiac death has been shown to be associated

with genetic electrophysiological abnormalities in K +,

Na + , and Ca2 + channels that affect the depolarization

and repolarization of cardiomyocytes (Keating & Sangui-

netti, 2001). In contrast, in mice lacking the gene for

Kir6.1, none of these abnormalities appeared in the plasma

membrane of cardiomyocytes. It also was shown that

cardiomyocytes of Kir6.1 knockout mice display normal

electrophysiological properties; the K +-channel opener

pinacidil produced an increase in outward current and a

shortened action potential duration. These effects were

reversed by glibenclamide, a KATP-channel blocker. The

effects were similar in wild-type and Kir6.1 knockout

mice. Accordingly, it is not likely that Kir6.1 is a subunit

of the plasma membrane KATP channels in cardiomyocytes.

These findings also indicate that the AV block in Kir6.1

knockout mice is not due to plasma membrane channel

dysfunction in cardiomyocytes. An alternative explanation

for the AV block and sudden cardiac death in Kir6.1

knockout mice is myocardial ischemia caused by impaired

regulation of vascular tonus of the coronary arteries.

Indeed, it has been shown that Kir6.1 knockout mice lack

a vasodilation response to K +-channel openers such as

pinacidil, both in vivo (blood pressure decrease) and in

vitro (relaxation of aortic rings) (Miki et al., 2002). Wild-

type mice as well as Kir6.2 knockout mice, in contrast,

exhibit similar vasodilation responses to K +-channel open-

ers, the effects of which were blocked by glibenclamide

(Suzuki et al., 2001). Intravenous injection of methylergo-

Fig. 1. Types of KATP channel.

S. Seino / Journal of Diabetes and Its Complications 17 (2003) 2–5 3

metrine directly triggers vasoconstriction-induced elevation

in ST segment and cardiac death in Kir6.1 knockout mice

but not in wild-type mice. The lack of vasodilation

response to K + -channel openers and the abnormal

response to a vasoconstrictor in Kir6.1 knockout mice

indicate that this KATP-channel subunit plays a critical role

in the regulation of vascular tone, especially in the

coronary arteries.

The most striking finding in Kir6.1 knockout mice is

severe, lethal AV block due to spontaneous coronary

spasm (Miki et al., 2002) (see Fig. 2). This closely

resembles Prinzmetal angina in humans, a form of

unstable angina associated with hypercontractility of

epicardial coronary arteries (Prinzmetal, Kennamer, Mer-

liss, Wada, & Bor, 1959). Prinzmetal angina is charac-

terized by ST-segment elevation during the anginal attack

or by induction of coronary spasm using ergot alkaloids

or acetylcholine (Maseri, 1987). As the sudden cardiac

death in Kir6.1 knockout mice was associated with

spontaneous ST-segment elevation and the ergot alkaloid

methylergometrine provoked significant elevations of the

ST segments both in vivo and in vitro in these samples,

Kir6.1 knockout mice may well be a suitable animal

model of Prinzmetal angina. The regulatory subunit of

Kir6.1 is the sulfonylurea receptor SUR (most likely

SUR2B). Sulfonylureas are widely used in the treatment

of Type 2 diabetes, so it is important to learn the

different effects of the agents of this therapeutic class

on the Kir6.1/SUR2B channel.

5. Conclusion

Studies using Kir6.2 and Kir6.1 knockout mice have

been essential in determining the physiological roles of

KATP channels. The role of Kir6.2/SUR1 in pancreatic

b-cells and Kir6.2/SUR2A in cardiomyocytes is well

established. Less clear, however, are the subunits which

constitute the KATP channel in vascular smooth muscle

tissue. Recent work on Kir6.1 knockout mice indicates

that Kir6.1, rather than Kir6.2, is required in the regu-

lation of vascular tone, in association with SUR2B. The

importance of the differing effects of the various sulfo-

nylureas on the different extrapancreatic KATP channels

is suggested.

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