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KCa1.1 (BK) - High throughput study

KCa1 1 SampleTracesicon sp96   SyncroPatch 384i data and applications:
Data kindly provided by Sharan R. Srinivasan1 and Vikram G. Shakkottai1,2
1Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
2Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.

HEK293 cells stably transfected with BK channels were used to screen over 50,000 compounds, and using clever buffering techniques, targeting only activators of calcium sensitivity for BK channel augmentation. 

Read more

 

 

 

KCa1 1 Srinivasan

 

Source:

Augmenting BK Channel Function as Therapy for Spinocerebellar Ataxia (SCA) (5571)
Neurology (2020) doi: 10.1172/JCI133398

Abstract: 

Objective:
Spinocerebellar Ataxias (SCA) are dominantly inherited disorders resulting in progressive ophthalmoplegia, dysarthria, and gait imbalance. In disease mouse models, large conductance calcium-activated potassium (BK) channel dysfunction is common to multiple polyQ SCAs. Restoration of BK channel expression and function results in improved motor function and delayed cerebellar degeneration. The goal of this work is to identify compounds that augment BK channel function as therapy for SCA.

Design/Methods:
Our work utilizes a state-of-the art automated patch clamp (APC) platform to perform high throughout drug screening. HEK293 cells stably transfected with BK channels were used on the SyncroPatch 384i platform. We are screening over 15,000 compounds, and using clever buffering techniques, targeting only activators of calcium sensitivity for BK channel augmentation. To confirm that BK channel kinetics are not altered with solutions used in this HTS, we will perform parallel manual patch-clamp recordings with conventional solutions.

Results:
In conjunction with Nanion Technologies, we have demonstrated feasibility of a BK channel screen using the SyncroPatch 384i. With a 2-component internal solution, seal rate is excellent and activated BK currents are maintained for up to 2.5 hours. The current could be blocked by TEA, and weakly augmented (as expected) by NS1619. These preliminary studies are indicative of a viable platform for HTS against BK and identification of both agonists and antagonists.

Conclusions:
Here, we introduce a next-generation APC platform for HTS to identify compounds that augment BK channel current in the presence of low intracellular calcium. The most promising agents will be further tested with dose-response curves and then confirmed by manual patch clamp. Future development will focus on improving drug-like properties with finalized compounds tested in SCA mouse models. In this manner, we will make significant progress towards specific therapy for this debilitating group of disorders. 

Authors:
Sharan R. Srinivasan1 and Vikram G. Shakkottai1,2
1Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
2Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.

Target: KCa1.1

Instrument:   icon sp96   SyncroPatch 384i

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