Respuesta farmacológica y estudio funcional de los canales KATP con mutaciones asociadas al Síndrome de Cantú

Résumé

KATP channels are blocked by physiological concentrations of ATP and generate repolarizing currents (IKATP) with inward rectification when levels of this intracellular mediator decrease. Therefore, they connect cellular metabolic and electrical activities in various tissues in which they are expressed (heart, pancreas, smooth and skeletal muscle, etc.). KATP channels are formed by the association of 4 α Kir6.1 and/or Kir6.2 subunits and 4 β SUR1 and/or SUR2 subunits. Cantu Syndrome (CS) is a rare disease (ORPHA:1408; OMIM #239850) caused by mutations in genes that encode Kir6.1 (KCNJ8) and SUR2A (ABCC9) subunits. Mutations decrease the channel's sensitivity to ATP and, consequently, increase the density of IKATP. KATP channels are blocked by sulfonylureas, which have two binding sites: "A", which covers transmembrane segments 14 and 15 of the SUR subunit, and site "B", which includes part of the intracellular loop 0 of the SUR2 subunit and part of the N-terminal end of the Kir6.x subunit. Glibenclamide blocks the channels by binding to both sites; however, there are drugs that block them by binding exclusively to site "A" (such as gliclazide) or site "B" (such as repaglinide). Glibenclamide has been proposed as a therapeutic option for patients with CS. However, our first hypothesis is that glibenclamide may not be useful in all patients, as the blockade of KATP channels will depend on the subunit in which the mutation is present and its location. Therefore, our first objective was to compare the effects of various blockers on native KATP channels and those presenting mutations associated with CS...