The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C.

K(2P)2.1 (TREK1) two-pore-domain potassium channels control electrical activity in the central nervous system (CNS) and in the heart. Auxiliary β subunits (Kvβ) increase functional K+ channel diversity in the CNS. Based on similar tissue distribution and common functional significance of Kvβ2 protein and K(2P)2.1 channels in neuronal excitability, we hypothesized that Kvβ2 subunits modulate K2P2.1 currents.

Mutations of the cyclic nucleotide binding domain (CNBD) may disrupt human ether-a-go-go-related gene (hERG) K(+) channel function and lead to hereditary long QT syndrome (LQTS). We identified a novel missense mutation located in close proximity to the CNBD, hERG R744P, in a patient presenting with recurrent syncope and aborted cardiac death triggered by sudden auditory stimuli. Functional properties of wild type (WT) and mutant hERG R744P subunits were studied in Xenopus laevis oocytes using two-electrode voltage clamp electrophysiology and Western blot analysis. HERG R744P channels exhibited reduced activating currents compared to hERG WT (1.48±0.26 versus 3.40±0.29μA; n=40). These findings were confirmed by tail current analysis (hERG R744P, 0.53±0.07μA; hERG WT, 0.97±0.06μA; n=40). Cell surface trafficking of hERG R744P protein subunits was not impaired. To simulate the autosomal-dominant inheritance associated with LQTS, WT and R744P subunits were co-expressed in equimolar ratio. Mean activating and tail currents were reduced by 32% and 25% compared to hERG WT (n=40), indicating that R744P protein did not exert dominant-negative effects on WT channels. The half-maximal activation voltage was not significantly affected by the R744P mutation. This study highlights the significance of in vitro testing to provide mechanistic evidence for pathogenicity of mutations identified in LQTS. The functional defect associated with hERG R744P serves as molecular basis for LQTS in the index patient.

There is increasing evidence supporting the role of platelets in atherosclerotic vascular disease. The G-protein-coupled receptor P2Y12 is a central mediator of platelet activation and aggregation but has also been linked to platelet-independent vascular disease. Ticagrelor is an oral P2Y12 antagonist that is used as a standard treatment in patients after acute myocardial infarction. However, the effects of ticagrelor on advanced atherosclerosis have not been investigated.

Two-pore-domain K(+) channels (K(2P) ) mediate K(+) background currents that modulate the membrane potential of excitable cells. K(2P) 18.1 (TWIK-related spinal cord K(+) channel) provides hyperpolarizing background currents in neurons. Recently, a dominant-negative loss-of-function mutation in K(2P) 18.1 has been implicated in migraine, and activation of K(2P) 18.1 channels was proposed as a therapeutic strategy. Here we elucidated the molecular mechanisms underlying PKC-dependent activation of K(2P) 18.1 currents.

Atrial fibrillation (AF) is the most frequently encountered sustained cardiac arrhythmia in clinical practice and a major cause of morbidity and mortality. Effective treatment of AF still remains an unmet medical need. Treatment of AF is based on drug therapy and ablative strategies. Antiarrhythmic drug therapy is limited by a relatively high recurrence rate and proarrhythmic side effects. Catheter ablation suppresses paroxysmal AF in the majority of patients without structural heart disease but is more difficult to achieve in patients with persistent AF or with concomitant cardiac disease. Stroke is a potentially devastating complication of AF, requiring anticoagulation that harbors the risk of bleeding. In search of novel treatment modalities, targeted pharmacological treatment and gene therapy offer the potential for greater selectivity than conventional small-molecule or interventional approaches. This paper summarizes the current understanding of molecular mechanisms underlying AF. Established drug therapy and interventional treatment of AF is reviewed, and emerging clinical and experimental therapeutic approaches are highlighted.

Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.