Targeting neuronal potassium channels to modulate excitability in CNS disorders
Kv7.2 and Kv7.3 (encoded by the KCNQ2 and KCNQ3 genes) are voltage-gated potassium channels that control neuronal excitability by regulating the resting membrane potential in the central nervous system.
Activation (opening) of these channels generates the "M-current," which hyperpolarizes the membrane and suppresses excessive neuronal firing. Conversely, inhibition of Kv7.2/7.3 channels renders neurons hypersensitive and hyperexcitable. Kv7.2/7.3 openers can, thus, terminate or reduce neuronal firing which makes them candidates for treatment of i.g. epilepsy and seizure disorders, neuropathic pain and other CNS diseased states.
Most Kv7.2/7.3 activators do not simply increase the maximum current amplitude; instead, they modulate channel kinetics by shifting the activation curve to more negative voltages. ChanPharm's assays, therefore, focus on estimation of drug-induced increase of the current amplitude and drug-induced gating shifts. To address safety and selectivity, potential drug candidates are rigorously counter-screened against other Kv channels, including Kv7.4 and Kv7.5 (e.g. activating Kv7.4 channels in the inner ear carries a significant risk of ototoxicity).
Several key drugs and tool compounds have been developed that open (activate) Kv7.2/7.3 channels:
SyncroPatch 384
Ion channel screening at scale.
The SyncroPatch 384 is a high-throughput automated patch clamp platform optimized for large-scale ion channel screening. For Kv7.2/7.3, it is ideal for parallel recordings across hundreds of cells to determine precise voltage activation shifts across large compound libraries.
Best suited for: Primary screening, hit confirmation, and early off-target assessment.
NANION TECHNOLOGIES HIGH THROUGHPUT
Patchliner
High-quality functional profiling with automation.
The Patchliner provides medium-throughput automated patch clamp recordings with excellent gigaseal quality. This is critical for detailed secondary screening and selectivity profiling against off-target channels like Kv7.4.
Best suited for: Secondary screening, lead optimization, mechanism-of-action studies.
NANION TECHNOLOGIES MEDIUM THROUGHPUT
Manual Patch Clamp
Gold-standard ion channel electrophysiology.
Manual patch clamp provides unmatched experimental control and resolution for studying ion channel function. This approach is used for deep mechanistic studies and intricate characterization of state-dependent channel modulation.
Best suited for: Detailed kinetics, complex protocols, validation of screening results.
CONVENTIONAL SYSTEMS GOLD STANDARD