Biology subjects

Chulkov, E. G.

Publications and source records attributed to Chulkov, E. G..

4 recordsLinked to original sources

bioRxiv2026

Clonazepam activates the transient receptor potential melastatin 8 (TRPM8) ion channel

Benzodiazepines represent a major class of drugs prescribed as treatments for anxiety, insomnia and seizures. They act by engaging GABAA receptors in the central nervous system to depress neuronal excitability. Here, the polypharmacology of benzodiazepines was explored by studying their engagement of human TRP channels revealing clonazepam acts as a robust and selective activator of the TRPM8 ion channel. Clonazepam-evoked Ca2+ signals were observed in cells expressing human TRPM8 channels, and in mouse trigeminal neurons. These responses were completely blocked by pharmacological or genetic inhibition of TRPM8 function. This discovery likely explains why clonazepam is an effective treatment for the painful oral condition known as burning mouth disorder, where local activation of TRPM8 channels in sensory neurons mitigates the painful symptoms of this disease.

neuroscience↗

bioRxiv2023

Target-based discovery of a broad spectrum flukicide

Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases - for example, the parasitic blood fluke infection, schistosomiasis - are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola. This is due to a single amino acid change within the target of PZQ, a transient receptor potential ion channel (TRPMPZQ), in Fasciola species. Here we identify benzamidoquinazolinone analogs that are active against Fasciola TRPMPZQ. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and damage to the protective tegument of these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPMPZQ orthologs in all profiled species of parasitic fluke. This broad spectrum activity was manifest as BZQ adopts a pose within the binding pocket of TRPMPZQ dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPMPZQ and a first-in-class, broad spectrum flukicide.

microbiology↗

bioRxiv2023

Praziquantel activates a native cation current in Schistosoma mansoni

Praziquantel (PZQ), an anthelmintic drug discovered in the 1970s, is still used to treat schistosomiasis and various other infections caused by parasitic flatworms. PZQ causes a triad of phenotypic effects on schistosome worms - rapid depolarization, muscle contraction, and damage throughout the worm tegument. The molecular target mediating these effects has been intimated as a Ca2+-permeable ion channel, but native currents evoked by PZQ have not been reported in any schistosome cell type. The properties of the endogenous PZQ activated conductance therefore remain unknown. Here, invasive electrophysiology was used to probe for responses to PZQ from different locales in a living schistosome worm. No direct response was seen in tegument-derived vesicles, or from the sub-tegumental muscle layer despite the presence of voltage-operated currents. However, PZQ rapidly triggered a sustained, non-selective cation current in recordings from neuronal tissue, targeting both the anterior ganglion and the main longitudinal nerve cord. The biophysical signature of this PZQ-evoked current resolved at single channel resolution matched that of a transient receptor potential ion channel named TRPMPZQ, recently proposed as the molecular target of PZQ. The endogenous PZQ-evoked current was also inhibited by a validated TRPMPZQ antagonist. PZQ therefore is a neuroactive anthelmintic, effecting a robust, depolarization through ion channels with the characteristics of TRPMPZQ. Key Findings / Scope StatementO_LIResponses to the anthelmintic drug, praziquantel (PZQ), were examined using invasive electrophysiology in a living schistosome worm. C_LIO_LIPZQ evoked a cation current in recordings from neuronal tissue C_LIO_LIThe biophysical and pharmacological characteristics of the native PZQ current matched the properties of TRPMPZQ. C_LI

pharmacology and toxicology↗

bioRxiv2021

Mechanism of praziquantel action at a parasitic flatworm ion channel

Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against the liver fluke Fasciola. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we show PZQ activates a transient receptor potential melastatin ion channel (TRPMPZQ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage-sensor like domain to cause Ca2+ entry and worm paralysis. PZQ activates TRPMPZQ homologues in other PZQ-sensitive flukes, but not Fasciola. However, a single amino acid change in the Fasciola TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the basis of PZQ action at a druggable TRP channel is resolved.

pharmacology and toxicology↗