SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator

Abstract

SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (K ATP ) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotidebinding domains of SUR results in an increase in K ATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.

LKB1 couples glucose metabolism to insulin secretion in mice

“…5b). However, the proportion of 13 C-labelling of citrate from glucose was similar in cells lacking LKB1, suggesting that tricarboxylic acid (TCA)-derived citrate from glucose was reduced, in a similar fashion to pyruvate. Following Lkb1 silencing, glucose flux to α-KG was also decreased, suggesting the excess pyruvate and citrate have an alternate fate besides cycling through the TCA cycle.…”

“…The central role of the K ATP channel in beta cell function is highlighted by deficiencies in both first and second phase GSIS in islets from sulfonylurea 1 (SUR1) −/− and ATP-sensitive inward rectifier potassium channel (KIR6.2) −/− mice [10]. In humans, inappropriate inhibition or activation of K ATP channel activity arising from mutations in KIR6.2 and SUR1 underlie congenital hyperinsulinaemia or neonatal diabetes, respectively [11][12][13].…”

Structural basis for allosteric cross-talk between the asymmetric nucleotide binding sites of a heterodimeric ABC exporter

“…The presented work offers a structural rationale for future studies on mammalian ABC exporters with asymmetric ATP-binding sites including the medically important transporters MRP1, SUR1, TAP1/2, and CFTR (33)(34)(35)(36).…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…To integrate the electrophysiological evidence that the cytosolic ATP/ADP ratio controls the open probability of the channel (reviewed in Refs. 11,133,422), with the glucoseregulated bioenergetic behavior of the intact ␤-cell, increasingly sophisticated techniques have been devised, starting with gross ATP determinations on cell or islet populations, then refined to whole-cell ATP/ADP ratios, compartmentselective monitoring of ATP in cell populations, and subsequently at single cell level, and most recently by exploiting probes that appear to monitor cytosolic ATP/ADP ratios directly.…”