Will the real K_ATP please stand up? Kir6.2/SUR2A takes the stand in the tiring case of skeletal muscle fatigue

When Noma reported in 1983 that potassium channels in cardiac muscle are closed by intracellular ATP (Noma, 1983), he was providing direct evidence for the first time for a beautifully simple idea: a potassium channel opens as the cell becomes metabolically stressed and limits further activity. It was also soon demonstrated that this current was sensitive to glibenclamide and active in pancreatic β-cells, providing a molecular explanation for the action of sulfonylurea drugs, which had been used since the late 1950s to stimulate insulin secretion (Cook and Hales, 1984). The K_ATP current was soon identified widely, including in all muscle types as well as in neurones (Spruce et al., 1985; Flagg et al., 2010). Patch-clamp recordings from frog skeletal muscle showed that the surface membrane carried these channels in remarkable abundance; by some estimates, they were the most densely expressed K⁺ channel of the sarcolemma (Spruce et al., 1985). Yet skeletal muscle promptly delivered a paradox that has shadowed the field ever since. Free [ATP] in working muscle is buffered by phosphocreatine to several millimolar—well above the IC₅₀ of the channel measured in excised patches—and therefore even during punishing exercise it falls by only about 20% (human data [Greenhaff et al., 1994]). From a simple bulk-ATP concentration perspective on paper, the sarcolemmal K_ATP channel should barely open. A succession of biophysical studies through the 1990s argued that the resolution lay in cofactors (e.g., acidification [Davies, 1990], adenosine, Mg-ADP, etc., reviewed by Flagg et al. [2010]) that modulate ATP sensitivity rather than simply [ATP] itself, but it has remained far from clear what physiological role the channel really had on skeletal muscle contractile behavior. Subtle changes in fatigue development were suggested to involve K_ATP, but without conclusive demonstration of the underlying molecular identity (Matar et al., 2000).

Part of the difficulty was that the K_ATP complex is itself, well, complex. The K_ATP channel family comprises a group of metabolically responsive proteins. Structurally, these channels are hetero-octameric complexes formed by four inwardly rectifying pore-forming subunits, Kir6.1 (encoded by Kcnj8) or Kir6.2 (encoded by Kcnj11), and four regulatory sulfonylurea receptor (SUR) subunits (part of the ATP-binding cassette protein family), which can be SUR1 (encoded by Abcc8) or SUR2 (encoded by Abcc9) with splice variants, SUR2A and SUR2B (Babenko et al., 1998).

Genetically, one might expect SUR1 and Kir6.2 to pair together since they both reside on chromosome 7 in mouse (Ensembl, 2026), and SUR2 to pair with Kir6.1 since these are both on chromosome 6 in mouse (Ensembl, 2026). All subunit types have been detected in skeletal muscle, with transcript profiles varying by species, fiber type, age, and pathological state, and patch-clamp work argues for tissue-specific hybrid assemblies in fast-twitch versus slow-twitch fibers (Tricarico et al., 2006). Correlation analysis of our own transcriptomic work with mouse skeletal muscle (Staunton et al., 2022) shows Kir6.1 correlates significantly with SUR2, the pairing described as “canonical” by Scala et al. (2026), but so too does the more abundantly transcribed Kir6.2 (Fig. 1). Perhaps in terms of muscle Kir6.2 pairings, the Kir6.2/SUR2 could be referred to as “functionally canonical” despite being trans-chromosomal. Furthermore, whilst direct evidence for the in vivo existence of channels containing heteromultimeric pore-forming or regulatory subunits remains limited, experimental observations support additional complexity. For example, overexpression systems have revealed channels with intermediate single-channel conductances between those reported for Kir6.1 (∼40 pS) and Kir6.2 (∼80 pS) (Cui et al., 2001).

Reconstituted Kir6.2/SUR2A channels, clearly the main cardiac/skeletal type, have a notably lower nucleotide sensitivity than other isoforms (Babenko et al., 1998), a property since attributed to SUR2A-specific structural features that disfavor activation by Mg-nucleotide (Masia et al., 2005). So perhaps the physiologically dominant isoform in skeletal muscle could simply be the K_ATP variant least in conflict with millimolar [ATP]?

This is the gap that Scala et al. (2026) now close. Using a panel of mice individually lacking selected subunit genes (Kir6.2, SUR1, or SUR2), they assess isolated extensor digitorum longus contractility under a high-frequency tetanic fatigue protocol supplemented by pharmacological intervention. Single twitch and single tetanus parameters are unchanged across all genotypes, consistent with K_ATP channels not being engaged at rest. In WT muscle, pharmacological inhibition with the pan-K_ATP channel blocker, glibenclamide, had little effect on single contractions and produced, at most, a modest “nonsignificant trend” toward delayed fatigue onset, but more strikingly it significantly increased resting force between contractions.

Now here is where it gets interesting; during repeated high-frequency tetanic stimulation (225 Hz for 300 ms, delivered every 2 s), a progressive decline in force was observed, serving as an index of fatigue. This decline was modestly delayed by glibenclamide treatment. In addition, an increase in basal, unstimulated force was evident between contractions, which the authors attribute to the loss of hyperpolarizing current mediated by Kir6.2/SUR2A channels. And the transgenic results? Under repeated tetanic stimulation, Kir6.2^−/− and SUR2^−/− muscles produce a similar phenotype to glibenclamide treatment: slowed loss of stimulated force, attenuated intra-tetanic fade, and progressive development of substantial unstimulated baseline force. SUR1^−/− muscles were indistinguishable from wild type by every measure; furthermore, glibenclamide produces no further change in Kir6.2^−/− muscles, where it should, of course, if any glibenclamide-sensitive Kir6.1-containing channels were participating.