Focused issue on KATP channels
SUR, ABC proteins targeted by KATP channel openers

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Abstract

The sulfonylurea receptor SUR is an ATP binding cassette (ABC) protein of the ABCC/MRP family. Unlike other ABC proteins, it has no intrinsic transport function, neither active nor passive, but associates with the potassium channel proteins Kir6.1 or Kir6.2 to form the ATP-sensitive potassium (KATP) channel. Within the channel complex SUR serves as a regulatory subunit which fine-tunes the gating of Kir6.x in response to alterations in cellular metabolism. It constitutes a major pharmaceutical target as it binds numerous drugs, KATP channel openers and blockers, capable of up- or down-regulating channel activity. We here review current knowledge on the molecular basis of the interaction of classical KATP channel openers (cromakalim, pinacidil, diazoxide) with SUR.

Introduction

ATP-sensitive potassium (KATP) channels are non-voltage-dependent, potassium-selective channels gated by the intracellular nucleotides ATP and ADP. Gating is complex and thought to reflect the static and dynamic nature of the cellular metabolic status [1]. Thus KATP channels are postulated to act as sensors of intracellular metabolism, tuning the potassium permeability, and therefore the electrical activity, of a cell to its energetic balance. These channels are present in most excitable cells. In pancreatic ß cells, they play a key role in coupling insulin secretion to plasma glucose [2]. In muscle and neuronal cells their function is not as firmly established but evidence is strengthening for an implication in the protective response to various metabolic insults [3], [4], [5].

The KATP channel is made up of two proteins: the ~160 kDa sulfonylurea receptor SUR [6] which is a member of the ATP binding cassette (ABC) transporter family, and a smaller ~40 kDa protein Kir6.2 [7], [8] or Kir6.1 [9], [10] which belongs to the inward rectifier K+ channel family. Four Kir6.x subunits assemble to form a K+-selective pore, which is constitutively associated to four SUR subunits [11], [12], [13], [14] (Fig. 1). The variable tissue-specific properties of KATP channels, including their pharmacology arise from the identity of the SUR isoform expressed in that tissue. Notwithstanding splicing variants, the known three isoforms are SUR1, SUR2A, SUR2B. It is a relief for researchers already overwhelmed by the complexity of the KATP channel that these isoforms do not mingle well: channels have either four SUR1 or four SUR2 [15], [16]. Nonetheless, channels incorporating both SUR2A and SUR2B are probably viable although their physiological existence remains to be demonstrated.

Channels containing isoform SUR1, which is predominant in neuronal cells and pancreatic ß-cells, are blocked with high affinity by sulfonylureas [17] and can be activated by only one type of openers, the venerable diazoxide and its offsprings, NNC 55-9216 [18], NN414 and NNC 55-0118 [19]. Coded by a distinct gene, the SUR2x muscle isoforms—SUR2A predominant in cardiac and skeletal muscles and its splice variant SUR2B found in smooth muscle—impart activation by the full range of potassium channel openers [20], [21], including diazoxide in certain conditions [22].

Section snippets

SUR, a member of the ABCC family

The ultrastructure of the KATP channel is unique for an ion channel as it is the only known instance of such an intricate partnership between members of the ion channel and ABC protein gene families. How and why these two prominent groups of transmembrane proteins colluded to produce the KATP channel is not entirely clear, to say the least? Kir6.x channels are already endowed with an inhibitory site for ATP [23], which is modulated by phospholipids [24], [25], [26]. SUR adds two nucleotide

KATP channel openers bind to SUR

The search for the mechanism of action of antihypertensive drugs revealed that some of these drugs acted by upregulating the potassium permeability of cells. Initial proofs concerned nicorandil [58], diazoxide [59] and cromakalim [60]. The development of the patch-clamp technique [61] enabled the discovery of KATP channels [62] and the demonstration that these channels were the target of potassium channel openers. This was first demonstrated for diazoxide, which when applied to patches from

Chimeric studies delineate the binding site for muscle KATP channel openers

Having established that openers bind to SUR proteins, the signature sequences responsible for such a binding need to be identified; much progress to this end has been achieved through the use of SUR1/SUR2 chimeras.

The use of chimeric constructs between homologous yet functionally distinct channel proteins to identify primary sequence elements associated with a given phenotype was pioneered by Numa et al. in their works on the structure–function relations of the nicotinic acetylcholine receptor

Diazoxide, a special case

The benzothiadizine diazoxide and its derivatives deserve to be treated separately from the other openers since, notwithstanding pinacidil at high concentrations as mentioned above, they are the only openers of SUR1-containing pancreatic KATP channels. Diazoxide also activates smooth muscle SUR2B-based channels—a property at the origin of its hypotensive action—but was thought at first to have no effects on the cardiac SUR2A/Kir6.2 channels. In view of this lack of effect on sarcolemmal

Towards a mechanism of action of KATP channel openers

If presenting a detailed model of the KATP channel is premature, it is not forbidden to envision a rough sketch of its mechanism (Fig. 7). Kir6.2 can be imagined as having a structure resembling KirBac1.1 [113], the only known full-length K+ inward rectifier channel crystallized. The overall architecture of SUR is not as certain: it is closer in sequence to MsbA than BtuCD (Fig. 2) but homology in the TMD1 and TMD2 domains is weak. Furthermore, there are doubts on how TMD and NBD domains

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