Herbal Folk Remedy Molecular Mechanisms Uncovered

Traditional herbal medicines used for centuries often have tangible physiologic and therapeutic value. Yet, for these remedies to be successful for the masses the underlying cellular and molecular properties need to be carefully teased out and assessed for safety and effectiveness. In that vein, investigators in the department of physiology & biophysics at the University of California, Irvine School of Medicine (UCI) have discovered the molecular basis for therapeutic actions of an African folk medicine used to treat a variety of illnesses and disorders including diabetes, pain, headaches, paralysis, and epilepsy.

The researchers studied the herbal medicine, a leaf extract from the shrub Mallotus oppositifolius, which has been used across Africa for centuries. Until now, the molecular mechanism was not completely understood. Findings from the new study – published recently in Science Advances through an article titled “Deconstruction of an African folk medicine uncovers a novel molecular strategy for therapeutic potassium channel activation” – found that two components of the Mallotus leaf extract bind to a previously unrecognized binding site on KCNQ1, a potassium channel essential for controlling electrical activity in many human organs, including the heart, kidneys, gastrointestinal tract, thyroid, and pancreas.

“Plants are a rich source of compounds that modulate ion channels. We discovered the compounds from the African folk medicine bind to a novel site, positioned between the channel pore and its voltage sensor,” explained lead study investigator Geoffrey Abbott, Ph.D., a professor at UCI. “In addition, we found one of the compounds is of a chemical class previously not recognized as a KCNQ channel opener. These dual discoveries may facilitate future development of safer, more effective drugs.”

The researchers screened individual compounds from the Mallotus leaf extract for KCNQ1 opening activity, confirming one previously known channel activator and discovering one entirely new activator. They then used computer modeling to identify the binding site for these drugs on KCNQ1 and confirmed this previously unrecognized site using functional studies of mutant KCNQ1 channels.

“We used pharmacological screening and electrophysiological analysis in combination with in silico docking and site-directed mutagenesis to elucidate the effects of M. oppositifolius constituents on KCNQ1, a ubiquitous and influential cardiac and epithelial voltage-gated potassium (Kv) channel,” the authors wrote. “Two components of the M. oppositifolius leaf extract, mallotoxin (MTX) and 3-ethyl-2-hydroxy-2-cyclopenten-1-one (CPT1), augmented KCNQ1 current by negative shifting its voltage dependence of activation. MTX was also highly effective at augmenting currents generated by KCNQ1 in complexes with native partners KCNE1 or SMIT1; conversely, MTX inhibited KCNQ1-KCNE3 channels. MTX and CPT1 activated KCNQ1 by hydrogen bonding to the foot of the voltage sensor, a previously unidentified drug site which we also find to be essential for MTX activation of the related KCNQ2/3 channel.”

The UCI team found that the new drug binding site they had discovered is present on a different type of channel, KCNQ2/3, which is found in the brain and linked to epilepsy and encephalopathy. Discovery of this new site could point the way to improved anti-epileptic drugs.

“Genetic disruption of KCNQ1 causes lethal cardiac arrhythmias and is also associated with gastric cancer, type 2 diabetes, and thyroid and pituitary gland dysfunction,” Dr. Abbott concluded. “KCNQ2/3 disruption causes epilepsy and severe developmental delay. Therefore, new strategies are needed to therapeutically activate these potassium channels and overcome the effects of genetic disruption. The discovery of novel botanicals that might help in KCNQ drug development strategies highlights the importance of protecting plant species that can produce novel therapeutics. Factors including habitat loss, over-collecting, and climate change are threatening this invaluable resource.”