Thermo Fisher Scientific

Electron and cryo-electron microscopy stories and solutions about the advancement of cellular and structural biology

  • Categories
    • Advancing Materials
    • Advancing Mining
    • AnalyteGuru
    • Analyzing Metals
    • Ask a Scientist
    • Behind the Bench
    • Biotech at Scale
    • Clinical Conversations
    • Examining Food
    • Identifying Threats
    • Illuminating Semiconductors
    • Life in the Lab
    • Life in Atomic Resolution
    • OEMpowered
    • The Connected Lab
  • About Us
  • Contact
Accelerating ScienceLife in Atomic Resolution / Customer Spotlights / Cryo-EM Reveals the Role of CNS Protein Complex Kv3.1 in Epileptic Disorders

Cryo-EM Reveals the Role of CNS Protein Complex Kv3.1 in Epileptic Disorders

By Alex Ilitchev 08.25.2022

Studying the causes and mechanisms of epileptic disorders

The human brain, for all its capability and potential, is ultimately controlled by a delicate balance of chemical signals. When these signals are disrupted, the consequences can range from minor symptoms to life-threatening disorders. Epilepsy describes a range of conditions where atypical brain activity causes seizures or other undesired behavioral symptoms. Researchers are constantly looking to deconvolute the causes and mechanisms of epileptic disorders in order to develop more effective, targeted treatments.

Neuron membrane proteins: a critical area of biomedical research

Speaking more specifically, neuronal signaling is regulated by the electrochemical activation of ion channels within the neurons’ cell membranes. Voltage-dependent potassium-ion channels, for instance, open in response to a particular membrane potential; the potassium ions pass through the channel in order to equilibrate the electrochemical gradient across the membrane, returning the cell to its resting state. This fundamental mechanism is what allows the neuronal cells of the central nervous system (CNS) to “reset” after communicating; it also makes CNS protein a critical area of biomedical research.

Using cryo-EM to better understand potassium channels and epileptic disorders

Voltage-dependent potassium-ion channels, particularly the Kv3 family that is encoded by the KCNC1 gene, have been implicated in a range of CNS diseases, including hereditary epilepsy disorders. Regulating their activation would require a clear understanding of their structures, as this reveals potential binding sites for therapeutic agents.

While crystallography has been the technique of choice for structural biologists, it is challenging to use on membrane protein complexes such as Kv3s, as they are resistant to crystallization. To overcome this barrier, researchers have turned to cryo-electron microscopy (cryo-EM) for structural analysis, as it can be used to analyze isolated proteins and complexes without the need for crystallization.

Kv3.1 protein complex in epileptic disorders

Kv3.1 in a membrane with potassium and chloride ions. Source: Katharina Dürr

Researchers determine high-resolution Kv3.1a potassium ion channel structure

In a recent Nature Communications publication, researchers at Oxford University led an effort to understand the structure of the Kv3.1a channel; mutations to this complex have been associated with severe epileptic disorders, but the exact mechanistic reason for this is still unknown.

Using cryo-EM, they were able to determine the structure of Kv3.1a to ~3.2 Å resolution. With this level of detail, they identified several binding sites for potential agonistic and antagonistic therapeutic agents. This included a previously unknown “control element,” a domain within the complex that has a significant impact on Kv3.1a channel gating.

These insights are a crucial first step towards structure-based drug design to alleviate the effects of several hereditary epileptic disorders. In a commentary piece that accompanied the research publication, CTO of Autifony Therapeutics Martin Gunthorpe shared this:

With respect to the translational potential of this work, it is encouraging that a number of companies are already developing Kv3 modulators and some of these have advanced into clinical development. In addition to the human genetically validated approaches identified, there are also additional opportunities in more prevalent diseases such as schizophrenia, Fragile X syndrome, and Alzheimer’s disease, supported by a growing understanding of the role of Kv3 channels in controlling neuronal activity in relevant cell types and circuits in the brain.


Read Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain in Nature Communications >>


Treating KCNC1-encoded ion channel disorders

Beyond just providing cryo-EM instrumentation for this project, our Thermo Fisher Scientific colleagues Mazdak Radjainia, Pu Qian and Pablo Castro-Hartmann worked with former colleague and now associate principal scientist at AstraZeneca Kasim Sader to collect critical data on the Kv3.1a complex in support of this research.

Their data resulted in high-resolution reconstructions of the channel bound to zinc ions. We are proud to play such an active role in this work and of the impact this research will have on therapeutic development.

Now that researchers have clear structures for this ion channel, they can investigate how they are impacted by genetic mutations to KCNC1. With a thorough understanding of the structural basis for Kv3.1a dysfunction, highly targeted treatments for epileptic disorders can be developed whose efficacy can be monitored down to the molecular level.

Recent studies highlight direct causal links between Kv3.1, Kv3.2 and Kv3.3 channel dysfunction and disease and it seems likely that it is only a matter of time for Kv3.4. These findings, together with the work of Chi et al., provide increased confidence in the validation and tractability of novel therapeutic approaches for Kv3 channels, including the development of precision medicines. It would therefore seem that the timing is right for recent advances in our understanding of ion channel structure, function and pharmacology to translate into new therapeutic approaches for channelopathies and other diseases with high unmet need.

-Martin Gunthorpe

 


Alex Ilitchev, PhD, is a Lead Scientific Editor at Thermo Fisher Scientific.

European Molecular Biology Laboratory

European Molecular Biology Laboratory a Key to Continued Tundra Cryo-TEM Innovation

Cryo-electron microscopy thrives at the European Molecular B...

Read More
Microscopy Today Innovation Award 2023

Thermo Scientific Arctis Cryo-PFIB Wins Microscopy Today Innovation Award

Arctis Cryo-PFIB wins Microscopy Today Innovation Award at M...

Read More
Cryo-EM facility leader Dr. Montserrat Samso

Cryo-EM Facility Leader at Virginia Commonwealth University Helps Bring One of the First Tundra Cryo-TEMs to the U.S.

Cryo-EM facility secures new transmission electron microscop...

Read More
Transmission electron microscopy simplified, showcased on Tundra Cryo-TEM tour

Thermo Fisher Scientific Hits the Road to Showcase Simplified Cryo-TEM

During the fall semester, we visited colleges and institutio...

Read More

Leave a Reply Cancel reply

Your email address will not be published. Required fields are marked *

Institute of Science and Technology Austria On the Advantages of Cryo-Electron Tomography (Vlog)
First In-Person Microscopy and Microanalysis (M&M) Event Since 2019 Brings Major Announcements, Revered Speakers, Awards and More

Privacy StatementTerms & ConditionsLocationsSitemap

© 2023 Thermo Fisher Scientific. All Rights Reserved.

Talk to us

Go to mobile version