CNS

The role of ion channels and transporters in neurological disease.

Brainstorming solutions: Navigating the complex world of neurological disease

The brain is the most complex organ in the body, using chemical, electrical and genetic signaling and structural remodeling to process and store information. Voltage- and ligand-gated ion channels and transporters control and modulate neurotransmitter release, re-uptake, and neuronal excitability. Mutations and functional changes in many of those ion channels and transporters are associated with common and rare diseases such as epilepsy and pain. Complex central nervous system (CNS) diseases such as autism, schizophrenia, depression, developmental syndromes, and neurodegeneration also include a role for ion channels in neurons, glia, and inflammatory microglia as early triggers of excitability changes or disease modifiers.

Ion channels control CNS

excitability and neurodegeneration

Ion channels is epilepsy

One of the major CNS diseases involving ion channels is epilepsy. There are thousands of mutations in NaV, CaV, and KCNQ channels and GABAA ionotropic receptors found in human patients, making it the 4th most common neurological disease. Gain-of-function mutations in excitatory NaV channels and loss-of-function mutations in inhibitory KCNQ channels are expected to promote epileptic seizures. However, the cellular context of each ion channel is also important. Gain-of-function mutations in NaV channels in excitatory neurons underlie specific forms of epilepsy (e.g. NaV1.2 in GEFS, NaV1.6 in DEE13 and SUDEP), but loss-of-function mutations in other NaV channels in inhibitory interneurons underlie patient seizures (e.g. NaV1.1 in Dravet syndrome). Researchers are therefore looking for both activators and inhibitors of CNS ion channels implicated in rare and common forms of epilepsy. High throughput patch clamp electrophysiology is essential for this work, both to enable a detailed biophysical study of numerous epilepsy ion channel mutations, and to facilitate the efficient screening and discovery of new ion channel ligands to prevent seizures.

Mechanisms of neurodegeneration

Neuronal hyperexcitability is an early symptom in neurodegenerative diseases and can lead to cell injury and death, which manifests as chronic and progressive neurodegeneration in patients suffering from Alzheimer’s, ALS, Parkinson’s disease, and frontotemporal dementia. Researchers are developing modulators of depolarising (e.g. NaV, CaV) and hyperpolarising (KV7.x) ion channels as a mechanism to control neuronal hyperexcitability and reduce neurodegenerative cell loss and dementia symptoms.

Another role for ion channels in neurodegeneration involves their regulation of lysosomal organelles. Changes in organelle ionic balance mediated by ion channels such as TMEM175, TRPML1, and TPC help regulate the recycling and degradation of faulty and toxic proteins by the ubiquitin-proteasome pathway, thereby removing protein tangles in neurodegenerative diseases. Also, genetic changes in organelle ion channels are associated with an increased risk of some CNS neurodegenerative and metabolic diseases, making them attractive targets for academic research and drug discovery. It is difficult to study ion channels in organelle membranes with traditional patch clamp techniques, but SURFE2R and Orbit platforms can achieve this with ease.

Automated patch clamp:
ideal technique to study

disease-related ion channel mutations

Profiling ion channel mutations in CNS

Challenges of studying CNS disease-related channelopathies, such as rapid profiling of many patient mutations and high-fidelity recordings to discriminate subtle biophysical changes in current density, channel kinetics, and voltage dependence, are very well addressed by automated patch clamp, such as Patchliner and SyncroPatch 384. Understanding the actual, rather than predicted, effect of ion channel mutations is required to categorize them as benign or pathophysiological, and guide drug treatment and clinical prognosis. Rapid acquisition of high-quality and information-rich patch clamp data on ion channel mutants also enables sophisticated machine learning and protein modeling methods to predict loss- or gain-of-function and pathogenicity. These methods have been successfully applied to NaV1.1, NaV1.2, NaV1.6, and KCNQ channel mutations from epilepsy patients, as well as channelopathies associated with other CNS neurological diseases such as schizophrenia, Alzheimer’s disease, autism, and intellectual disability.

Accelerating Ion Channel Characterization and New Drug Candidate Identification

Speakers:

Alfred George, M.D.
Chair, Department of Pharmacology, Northwestern University Feinberg School of Medicine

Matt Fuller, Ph.D.
Senior Scientist, Icagen

Organisation: Icagen Inc.

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