These results shed light on the pathophysiologic relevance of SUR2-dependent KATP channel subunits in skeletal muscle and highlight their role in fatiguing conditions. (6/n)

These effects could be prevented in the presence of the KATP channel inhibitor glibenclamide, indicating that the increased fatigue of isolated muscles is a direct consequence of overactive sarcolemmal KATP channels. (5/n)

Ex vivo testing of isolated SUR2[A478V], but not Kir6.1[V65M], muscles showed an early onset of fatigue and a marked intra-tetanic decline of force. (4/n)

Direct consequences of CS mutations on sarcolemma KATP channels on muscle contractility are currently unclear. Here, we assessed contractility in isolated fast- and slow-twitch muscles from two mouse models of CS, carrying GOF mutations Kir6.1[V65M] or SUR2[A478V]. (3/n)

Cantu syndrome (CS) is a rare disease caused by gain-of-function (GOF) mutations of Kir6.1 or SUR2 subunits of ATP-sensitive potassium (KATP) channels. CS patients display a constellation of symptoms, including muscle weakness and fatigue. (2/n)

These motions are reduced when PIP2 is removed, leading to narrowing of the critical gate at the M2 helix bundle crossing (HBC), but expansion at the region G-loop, as well as reduced overall fourfold symmetry, in turn coupled to cessation of ion permeation. (5/n)

We have carried out full atomistic MD simulations, which indicate PIP2-dependent conformational changes that are coupled to opening and closing of the channel. In the presence of bound PIP2, the cytoplasmic domain performs clockwise twisting motions. (4/n)

Most Kir2 channel structures determined in complex with PIP2 molecules are in a closed state, requiring additional conformational changes for channel opening. (3/n)

Inwardly rectifying potassium (Kir) channel activity is important in the control of membrane potentials and is regulated through various ligands, including Phosphatidyl-4,5-bisphosphate (PIP2)(2/n)

Our data provide definitive support for a paradoxical form of MODY associated with KATP channel LOF that is genetically and mechanistically distinct from a late diagnosis of neonatal diabetes resulting from KATP GOF. (5/n)

In contrast to the naïve prediction that diabetes should be associated with KATP gain-of-function (GOF, as in KATP-dependent neonatal diabetes), each mutation caused mild to severe loss-of-function (LOF), through distinct molecular mechanisms. (4/n)

We report genotype-phenotype information from a set of patients clinically diagnosed with maturity-onset diabetes of the young (MODY) and carrying coding variants in the KATP regulatory subunit gene ABCC8. (3/n)

Pancreatic β-cell ATP-sensitive K+ (KATP) channel closure underlies electrical excitability and insulin release, but loss or inhibition of KATP channels can lead to paradoxical crossover from hyperinsulinism plus hypoglycemia, to glucose intolerance or diabetes. (2/n)