Ion channels are complex proteins that control the flow of ions across cell and organelle membranes. They can be gated by transmembrane voltage or neurotransmitters, and respond to endogenous ligands or environmental agents. Ion channels are present in every cell type and thereby control neuronal excitability, cardiac, skeletal, and smooth muscle contraction, and hormone release. Their ubiquitous location and varied function, alongside genetic mutations associated with many human diseases, make them attractive drug discovery targets. Exploring ion channel function has yielded successful therapeutics for pain, epilepsy, diabetes, and cardiac and vascular disease.
Ion channels are divided into voltage- and ligand-gated families, with unique voltage sensor, ligand-binding and pore domains. Each subunit consists of four to six transmembrane domains, and three, four or five combine as homo or heteromers to create ion channels with varied biophysics and pharmacology. As well as ligands and voltage, other stimuli such as pressure/stretch and temperature can activate certain ion channels.
The widespread expression and specialized function of ion channels make them important targets for neuroscience, neurodegeneration, hormone secretion, muscle function, cardiac safety, and cancer.
Patch clamp electrophysiology remains the gold standard for studying complex biophysical properties of ion channels, and for investigating state-dependence and selectivity of ion channel modulators. However, conventional patch clamp is notoriously low throughput and requires skilled personnel to perform the experiments. Automated patch clamp has emerged as a viable alternative to conventional patch clamp and enables rapid and high throughput testing of single disease-related mutations in large ion channel proteins to improve disease diagnosis and treatment based on precise biophysical and pharmacological profiling. Large compound libraries can be screened in a short amount of time and selectivity and safety experiments can be performed with ease and at high throughput. Combining electrophysiology with other techniques such as cryo-EM and impedance can also provide extra information about the interaction of molecules with ion channels and their knock-on effects on cell health and contractility.
The recording of ligand-gated ion channels requires fast and precise application of external ligand. This is achieved on the Port-a-Patch via the External Perfusion System, and on the Patchliner and SyncroPatch 384 by stacking solutions inside the pipettes and rapid application of ligand using a high pipetting speed. Recording of voltage-gated ion channels requires good whole-cell access and accurate voltage control which is achieved through the borosilicate glass chips, suction application to get good whole-cell access, and high-quality amplifiers. Sophisticated experiments involving rapid and transient heat activation of TRP channels can be performed using the temperature control of the Patchliner, whilst heat and cold activation of channels can be done on the Port-a-Patch and SyncroPatch 384. Pressure activation of ion channels can be achieved using suction or shear stress via the pipette. With the automated patch clamp instruments from Nanion, molecules and ions can be easily applied in the internal solution thereby facilitating research on Ca2+ or Na+-activated ion channels.
PIEZO channels are mechanically activated cation channels, mediating various health and disease mechanisms such as red blood cell homeostasis, malarial resistance, vascular structure and function, and lymphoedema. The 2021 Nobel Prize for Physiology or Medicine was awarded in part for the discovery of ion channels responsible for touch, recognizing their crucial role in physiology and pathophysiology. A bottleneck in drug development targeting PIEZO channels has been the lack of patch clamp systems capable of applying mechanical stimulation in an automated, higher throughput manner. Nanion’s Patchliner enables mechanical stimulation of PIEZO1 channels in an automated patch clamp instrument, allowing for reliable quantification of PIEZO1 activation by fluid flow and Yoda1.
We provide a range of electrophysiology platforms to study ion channels in native and heterologous cells and membranes:
These platforms can be used to study basic mechanisms of ion channel function, their role in cellular physiology, effects of patient and disease-derived mutations (channelopathies), and screen for new drugs.
Contact our specialist Dr. Alison Obergrussberger (Scientific Communications Manager). Alison is delighted to help you: