N-terminal transmembrane domain of the SUR controls trafficking and gating of Kir6 channel subunits

Abstract

The sulfonylurea receptor (SUR), an ATP-binding cassette (ABC) protein, assembles with a potassium channel subunit (Kir6) to form the ATP-sensitive potassium channel (K ATP ) complex. Although SUR is an important regulator of Kir6, the speci®c SUR domain that associates with Kir6 is still unknown. All functional ABC proteins contain two transmembrane domains but some, including SUR and MRP1 (multidrug resistance protein 1), contain an extra N-terminal transmembrane domain called TMD0. The functions of any TMD0s are largely unclear. Using Xenopus oocytes to coexpress truncated SUR constructs with Kir6, we demonstrated by immunoprecipitation, single-oocyte chemiluminescence and electrophysiological measurements that the TMD0 of SUR1 strongly associated with Kir6.2 and modulated its traf®cking and gating. Two TMD0 mutations, A116P and V187D, previously correlated with persistent hyperinsulinemic hypoglycemia of infancy, were found to disrupt the association between TMD0 and Kir6.2. These results underscore the importance of TMD0 in K ATP channel function, explaining how speci®c mutations within this domain result in disease, and suggest how an ABC protein has evolved to regulate a potassium channel.

Functional Dissection of the Transmembrane Domains of the Transporter Associated with Antigen Processing (TAP)

“…However, extra N-terminal extensions can be found. For example, the N-terminal domain (TMD 0 ) of the sulfonylurea receptor, which is associated with persistent hyperinsulinemic hypoglycemia of infancy, recruits the potassium channel subunit K IR 6.2 (37,38).…”

Role of the NH2-terminal Membrane Spanning Domain of Multidrug Resistance Protein 1/ABCC1 in Protein Processing and Trafficking

“…Alternatively, only MRP1 MSD0 may be able to establish interactions necessary for the COOH-terminally truncated or mutated proteins to exit the ER. Whether these interactions are exclusively with the core of MRP1 or involve another protein, as shown for the SURs (Babenko and Bryan, 2003;Chan et al, 2003), is under investigation. …”

“…The cytoplasmic NH 2 termini of ABCC proteins lacking MSD0 show some conservation of sequence with the start of CL3 in proteins such as MRP1, suggesting that the additional MSD may have been acquired by fusion of a gene encoding a core ancestral ABCC protein with one or more genes encoding other integral membrane proteins . Presently, a functional role for the NH 2 -terminal MSD has been best characterized in stud- ies of SUR1, where an interaction between MSD0 and the potassium channel, Kir6.2 is required for K ATP -channel plasma membrane trafficking and gating (Otonkoski et al, 1999;Babenko and Bryan, 2003;Chan et al, 2003). In addition, the NH 2 -terminal MSDs of MRP2 and the yeast MRP1 orthologue, Ycf1, are necessary for apical membrane and vacuolar localization, respectively (Fernandez et al, 2002;Mason and Michaelis, 2002).…”

cAMP-dependent Protein Kinase Phosphorylation Produces Interdomain Movement in SUR2B Leading to Activation of the Vascular KATP Channel

“…Such interaction has been observed in recombinant Kir6.2/SUR1 channels using electronic microscopy (30). Moreover, the TMD0 and ICL0 are involved in K ATP gating by channel modulators and nucleotides (31,32). Therefore, signals of NBDs must be coupled to TMDs to fulfill channel gating.…”