Review. 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 (KATP) 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 nucleotide-binding domains of SUR results in an increase in KATP 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.

Figure 1

SUR1 structure. (a) Membrane topology of SUR1. Residues mutated in HI are shown in green. The Walker A motifs are shown in purple, the Walker B motifs in orange and the ABC signature sequence (linker) motif in blue. (b) Homology model of the SUR1 NBD dimer. NBD1 is coloured bronze and NBD2 grey. Conserved motifs are colour coded as in (a). ATP is shown in green and Mg²⁺ in white.

Figure 2

Binding of TMD0 to Kir6.2ΔC—effect of the Y195E mutation. Co-immunoprecipitation from oocytes of FLAG-tagged TMD0 by HA-tagged Kir6.2. Oocytes were injected with cRNA for the relevant constructs and lysed after 2 days of incubation. Anti-HA antibodies were used to immunoprecipitate expressed Kir6.2ΔC. Precipitates were resolved on SDS-PAGE and transferred to nitrocellulose by western blotting. TMD0 bound to Kir6.2 was detected with anti-FLAG antibody. The extent of binding was quantified with densitometry and normalized to expression levels of both Kir6.2ΔC and TMD0. Data are mean±s.e.m. of three experiments. Bands below are typical western blot results.

Figure 3

Role of K_ATP channels in insulin secretion. (a) When metabolism is low, K_ATP channels are open, keeping the membrane hyperpolarized and voltage-gated Ca²⁺ channels closed, so that [Ca²⁺]_i remains low and insulin secretion is prevented. (b) When metabolism increases, ATP increases and MgADP falls, closing K_ATP channels. This triggers depolarization of the β-cell, opening voltage-gated Ca²⁺ channels, and initiating Ca²⁺ influx and insulin release. (c) Loss-of-function mutations in SUR1 cause HI by producing permanent K_ATP channel closure, continuous membrane depolarization and Ca²⁺ influx, and thus persistent insulin secretion. (d) Gain-of-function mutations in SUR1 result in a failure of K_ATP channel closure when metabolism rises, so that the β-cell remains hyperpolarized even when blood glucose levels are elevated, keeping voltage-gated Ca²⁺ channels closed and preventing insulin secretion. This leads to diabetes.

Figure 4

SUR1 mutations enhance K_ATP currents and cause neonatal diabetes. (a) Disease severity correlates with the extent of unblocked K_ATP current measured in inside-out patches at 3 mM MgATP. The number of patches varies from five to nine. Data are taken from Proks et al. (2006a), Ellard et al. (2007) and Shield et al. (2008). (b) Relative incidence of ND subtypes caused by (i) SUR1 and (ii) Kir6.2 mutations.

Figure 5

Location of ND mutations. (a) Schematic of the membrane topology of SUR1 showing the location of ND mutations. Regions predicted to be helices are indicated as boxes. Residues causing neonatal diabetes are indicated in red. (b) Location of ND mutations in site 2.