Myrsinane, Premyrsinane, and Cyclomyrsinane Diterpenes from Euphorbia falcata as Potassium Ion Channel Inhibitors with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effects

Abstract

GIRK channels are activated by a large number of G protein-coupled receptors and regulate the electrical activity of neurons, cardiac atrial myocytes, and β-pancreatic cells. Abnormalities in GIRK channel function have been implicated in the pathophysiology of neuropathic pain, drug addiction, and cardiac arrhythmias. In the heart, GIRK channels are selectively expressed in the atrium, and their activation inhibits pacemaker activity, thereby slowing the heart rate. In the present study, 19 new diterpenes, falcatins A-S (1-19), and the known euphorprolitherin D (20) were isolated from Euphorbia falcata. The compounds were assayed on stable transfected HEK-hERG (Kv11.1) and HEK-GIRK1/4 (Kir3.1 and Kir3.4) cells. Blocking activity on GIRK channels was exerted by 13 compounds (61-83% at 10 μM), and, among them, five possessed low potency on the hERG channel (4-20% at 10 μM). These selective activities suggest that myrsinane-related diterpenes are potential lead compounds for the treatment of atrial fibrillation.

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

“…Excessive and repeated abnormal discharge of brain neurons represents the foremost feature associated with epilepsy, with the clinical manifestation manifested by transient central nervous system (CNS) dysfunction syndrome. 1 Abnormal discharge of neurons is closely linked with the dysfunction of potassium channels. 2 Various gene expressions, multiple signaling pathways, and multiple downstream proteins have all been implicated with the pathological changes associated with epilepsy.…”

Isolation and Pharmacological Investigation of Compounds From Euphorbia matabelensis

“…All compounds were studied for their antiproliferative activity against human tumor cell lines of gynecological origin, and GIRK channel-inhibitory activity using automated patchclamp method, as previously several diterpene esters, isolated by our group, possessed such pharmacological activities. 9,10 The fresh plant material (root [R] and stem [S]) of E. matabelensis (1.6 kg [R] and 0.9 kg [S]) was chopped and extracted with methanol at room temperature. After concentration, the extracts were dissolved in 50% aqueous methanol, and solvent-solvent partitions were performed with CHCl 3 and EtOAc.…”

“…All compounds were studied for their antiproliferative activity against human tumor cell lines of gynecological origin, and GIRK channel-inhibitory activity using automated patch-clamp method, as previously several diterpene esters, isolated by our group, possessed such pharmacological activities. 9,10…”

GIRK channel activity of Hungarian mushrooms: From screening to biologically active metabolites

“…Experiments were carried out on HEK-293 (human embryonic kidney) cells stably expressing the GIRK1/4 (Kir3.1/3.4) K + channels by adapting a method described earlier [21]. Cell line originated from UCL Business Plc.…”

“…hERG measurements were performed on HEK-293 cells stably transfected with cDNA encoding the hERG (Kv11.1) K + channel as described earlier in detail [21,22]. Cell line was purchased from Cell Culture Service (Hamburg, Germany).…”