K_ATP channel gain-of-function leads to increased myocardial L-type Ca²⁺ current and contractility in Cantu syndrome

Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) K_ATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca²⁺ current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascularspecific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in K_ATP GOF models is paralleled by changes in phosphorylation of the pore-forming α₁ subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased K_ATP current and CS cardiac pathophysiology.