Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

Abstract

ATP-sensitive potassium channels (K_ATP channels) play pivotal roles in excitable cells and link cellular metabolism with membrane excitability. The action potential converts electricity into dynamics by ion channel-mediated ion exchange to generate systole, involved in every heartbeat. Activation of the K_ATP channel repolarizes the membrane potential and decreases early afterdepolarization (EAD)-mediated arrhythmias. K_ATP channels in cardiomyocytes have less function under physiological conditions but they open during severe and prolonged anoxia due to a reduced ATP/ADP ratio, lessening cellular excitability and thus preventing action potential generation and cell contraction. Small active molecules activate and enhance the opening of the K_ATP channel, which induces the repolarization of the membrane and decreases the occurrence of malignant arrhythmia. Accumulated evidence indicates that mutation of K_ATP channels deteriorates the regulatory roles in mutation-related diseases. However, patients with mutations in K_ATP channels still have no efficient treatment. Hence, in this study, we describe the role of K_ATP channels and subunits in angiocardiopathy, summarize the mutations of the K_ATP channels and the functional regulation of small active molecules in K_ATP channels, elucidate the potential mechanisms of mutant K_ATP channels and provide insight into clinical therapeutic strategies.

Keywords: KATP channels; channelopathy; mitoKATP channels; mutation; myocardial ischemia; small active molecules.

FIGURE 1

The Structure of the K_ATP Channel. (A). K_ATP channels are comprised of four sulfonylurea receptors (SURx) and four K⁺ inward rectifiers (Kir6. x) that assemble to form hetero-octameric protein complexes. The green and pink sections on the left represent the side view of the Kir6. x subunit, and the gold and purple sections on the right represent the side view of the SURx subunit. FASTA comes from NCBI, designed by www.swissmodel.com, Image designed by Swiss-Pdbviewer software. (B). The pore-forming subunit Kir6. x (Kir6.1 and Kir6.2) has intracellular N- and C-termini and two transmembrane segments M1 and M2, encoded by KCNJ8 and KCNJ11, respectively. The modulatory subunit SURX (SUR1, SUR2A, SUR2B) consists of three groups of transmembrane domains (TMD0, TMD1 and TMD2) and extracellular N- and intracellular C-termini, encoded by ABCC8 and ABCC9. There are two intracellular nucleotide binding folds (NBD1 and NBD2) within the SUR subunit. ABCC8 and KCNJ11 are adjacent to each other on chromosome 11p15.1, with ABCC9 and KCNJ8 on chromosome 12P12.1.

FIGURE 2

The role of mitoK_ATP in myocardial ischemia and the regulation of the signaling pathways involved. (A). Mitochondrial injury and mitoK_ATP play a role in cardiac protection during the process of MIRI; MIRI increased Bax expression and decreased BCL₂ expression, triggering a cascade involving increased NO production and leading to the superficial formation of ONOO⁻ with increased production of ROS. Activation of mitoK_ATP stimulates the anti-inflammatory and antioxidant effects of NO on ischemic myocardium by inhibiting the overproduction of ROS. Ischemic postadaptation activates protein kinase C and the reperfusion injury salvage kinase pathway through the intracellular concentration of adenosine and NO, and it acts on the mitoK_ATP channel to protect the myocardium; activation of the mitoK_ATP channel leads to cell hyperpolarization, resulting in reduced Ca²⁺ entry, and a reduced driving force of mitochondrial calcium uptake, prevent Ca²⁺ accumulation in the matrix and MPTP formation. The MPTP is the escape pore of ROS, Cyt C, Ca²⁺ and other signaling molecules. CF indicates cardiac fibroblasts; MF, myofibroblasts; MIRI, myocardial ischaemia reperfusion injury; and ONOO⁻, peroxynitrite. (B). The structure of MPTP; F1Fo ATP synthase: The Fo subunit consists of a, e, f, g and A6 L, the F1 component consists of α and ß subunits, labeled in bottle green and yellow, respectively, and the γ, ε subunits. The F1 peripheral stalk is comprised of subunits b, d, F6, and OSCP. The C cyclic subunit, ANT and PiC are overlaid by IMM; the dotted line represents the MPTP signal molecule outflow position. OSCP indicates oligomycin sensitivity conferring protein; IMM, inner mitochondrial membrane; ANT, adenine nucleotide translocase; and PiC, phosphate carrier. (C). mitoK_ATP channels prevent transdifferentiation of CF to MF to reduce MF maturation. Testosterone (10 μM) increases the opening probability of mitoK_ATP channels, PHC regulates the mitochondrial K_ATP channel, Akt/GSK-3β, and Akt/mTOR signaling pathways, GST depends on protein-kinase C and mitoK_ATP channel pathway activation by some typical pathways such as PI3K/Akt and NO synthases, and plays roles in cardioprotection. Uridine attenuates myocardial injury and oxidative stress by activating the mitoK_ATP channel to reduce excessive ROS production and prevent calcium overload. PHC indicates penehyclidine hydrochloride; GST, genistein.

FIGURE 3

The functional regulation of active small molecules on K_ATP channels. (A) H₂S participates in K_ATP channel regulation. H₂S acts on the corresponding organ/tissues/cytochemical small molecules in the oval through K_ATP channels to produce physiological effects in a rectangular box. The black up and down arrows inside the ellipse represent increasing and decreasing, respectively. (B). NO participates in K_ATP channel regulation. The relative drugs in the ellipses produce physiological effects in the rectangular boxes through the K_ATP channels and NO/CGMP signaling pathways, which the reaction goes in the direction of the arrows in the same color. (C). O₂ participates in K_ATP channel regulation. Hypoxia results in a decrease in ATP/ADP acting on K_ATP channels to prevent action potential generation and cell contraction; The K_ATP channel acts on skeletal muscle and affects O₂ transport to sustain submaximal exercise tolerance; The K_ATP channel affects anterior cerebral circulation and total cerebral perfusion through O₂ transport to prevent action potential generation and cell contraction. The black up and down arrows inside the ellipse represent increasing and decreasing, respectively. (D). Other small active molecules. CORM-3 can mimic the HO-1/CO pathway, activate mitoK_ATP channels and elicit cardioprotection against hypoxia-reoxygenation injury by inhibiting the Na⁺/HCO₃ ⁻ transporter; CORM-2 alleviates gastric lesions at the systemic level via K_ATP channels, reducing gastric DNA oxidation and inflammatory responses; SO₂ plays a vasodilatory role through K_ATP channel activation in the peripheral cardiovascular system at high concentrations (>500 μmol/L).