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NINDS Workshop Targets Channelopathy


NINDS Workshop Targets Channelopathy
November 20 - 22, 2002
Gaithersburg, MD


Ion channels are the most basic elements of neuronal function. Proper structure, expression, localization and regulation of these channel proteins are essential for their normal activity. Abnormalities of ion channels contribute to many diseases that are now generically categorized as channelopathies. While channelopathies are broadly investigated in heart, kidney, and skeletal muscle, these disorders are seriously understudied in the central nervous system.

In order to encourage and support neural channelopathy research, NINDS sponsored a Channelopathy Workshop on November 20-21, 2002. Participants, composed of basic channel researchers, molecular and human geneticists, clinical neurologists, and representatives from the pharmaceutical industry convened to discuss the scientific challenges and technical barriers confronting neural channelopathy research as they relate to the genetics of disease (from gene mutations to transcriptional variants), functional identification of channel anomalies (by the use of new technologies and bioinformatics), and approaches to targeting and treating channelopathies (from small molecules to gene therapy).


Session I

Dr. Dennis Choi opened the workshop by delivering the keynote address on translating channelopathy research into drug development. The first session, chaired by Dr. Alfred George, Jr., focused on the genetic complexity of neural channelopathies. This complexity only partially arises from the vast pool of genes expressed in the multitude of different brain areas. Other factors that contribute to gene expression include post-translational processing of ion channel transcripts, such as alternative splicing and RNA editing. Protein trafficking affects where and when channels are expressed, and anomalies in this process can result in channelopathies. As channels and receptors are often dynamically expressed on the surface, the subcellular distribution of the channel is another important factor to consider.


Session II

The second session of the workshop, chaired by Dr. Henry Lester, outlined new approaches and technologies that are ready to be applied in channelopathy research. Comparative genomics is a newly emerging field that is leading to the identity of new mammalian ion channels. An example is the identification of channels in mammals as orthologs of channels in the nematode worm, C. elegans. One can also identify novel channels by searching for conserved motifs in an anonymous sequence database, and then use filter arrays to determine relative expression levels of channel subunits. Proteomics approaches, such as the use of mass spectrometry to analyze protein and peptide, are also gaining popularity. Such approaches can be used to determine the phosphorylation states of proteins, and to analyze protein-protein interactions. Another newly available technology that can expedite the analysis of channel function is planar patch-clamp recording for high-throughput electrophysiology. Conditional protein expression (knockouts and/or knockins) technology can be used to overcome embryonic lethality or to overexpress proteins in a spatiotemporal manner in otherwise normal animals or both.


Session III

The final session of the workshop, chaired by Dr. Jeffrey Noebels, addressed novel imaging approaches to high-throughput screening of channel function, including directed and random insertions of fluorescent proteins, screening proteins in affected tissues, and fluorescence resonance energy transfer (FRET) assays. This session also focused on the development of new therapeutic strategies for CNS channelopathy, including the search to identify compounds that alter channel function, such as use-dependent or small molecule modulators. It is also possible to use transgenic techniques to express modified ion channels to improve neural function. Targeted gene transfer using viral vectors is yet another way to modify channels in neural tissue.



The workshop attendees made several recommendations to NINDS to facilitate neural channelopathy research. These included providing increased infrastructure and technical staff support, assisting with the development and validation of disease-relevant animal models, encouraging collaborations among basic researchers, clinicians, and industry, supporting multidisciplinary approaches, and assisting with the determination of single nucleotide polymorphisms (SNPs) in ion channel sequences in control and patient populations.

While NINDS will consider these recommendations, the best progress is often made through investigator- and community-initiated efforts. Since the estimated cost of getting new drugs to market is about $800 million dollars per drug for large pharmaceutical companies, therapies for small and medium markets, which include the diseases caused by altered channels, are often not pursued. In some instances, smaller biotech companies are able to develop and market drugs for a small patient pool. To foster the development of treatments for channelopathies, NINDS encourages collaborations between basic scientists and clinicians so that disease mechanism and treatment can be matched to the patient. NINDS encourages research in a number of key areas: multidisciplinary collaborations in epilepsy research, translational programs, and center core grant programs to support neuroscience research. For more information on these funding initiatives and others, please see




NINDS Workshop: Channelopathy
November 20-21, 2002
Marriott Washingtonian Center Hotel
Gaithersburg, MD

Day 1: November 20, 2002
8:30 - 9:00Breakfast
9:00 - 9:10Opening Remarks: Audrey Penn, NINDS Acting Director
9:10 - 9:30Keynote: Dennis Choi, Merck
Translating Channelopathy Insights into Drugs

Session I. From Gene to Disease (Chair: Alfred George Jr.)

9:30 - 10:00Robert Reenan, University of Connecticut
Post-Transcriptional Processing of Ion-Channel Transcripts
10:00 - 10:30Louis Ptacek, University of Utah
Channelopathies: Extension from Muscle to the CNS
10:30 - 10:45Coffee Break
10:45 - 11:15Lily Yeh Jan, University of California San Francisco
Traffic Matters
11:15 - 11:45Morgan Sheng, Massachusetts Institute of Technology
Channelopathy Without Channelopathy - The Importance of Location
11:45 - 12:45Summary and Discussion
Lead: Alfred George Jr., Vanderbilt University
Pathophysiological Mechanisms on Channelopathies
1:00 - 2:00Lunch

Session II. From Gene to Function (Chair: Henry Lester)

2:00 - 2:30Lawrence Salkoff, Washington University
How the Comparitive Genomic Approach Led to the Identity of the Mammalian Sodium-Activated Potassium Channel
2:30 - 3:00Ewen Kirkness, Institute for Genomic Research
Identifying Novel Ligand-Gated Ion Channels and Their Expression Patterns
3:00 - 3:30Edward Cooper, University of PennsylvaniaProteomic Approaches for Studying Channel Regulation
3:30 - 4:00Coffee Break
4:00 - 4:30Fred Sigworth, Yale UniversityPlanar Patch-Clamp Technology and the Prospects for High-Throughput Electrophysiology
4:30 - 5:00Joe Tsien, Princeton University
Conditional Protein Knockout Approach to Learning and Memory in Mice
5:00 - 6:00Summary and Discussion
Lead: Henry Lester, California Institute of Technology
Application of New Technologies in Channelopathy Research
7:00No Host Dinner at Rico y Rico
Day 2: November 21, 2002

Session III. From Gene to Therapy (Chair: Jeffrey Noebels)

8:00 - 8:30Breakfast
8:30 - 9:00Vincent Pieribone, Yale University
Reporting Channel Function by Fluorescent Protein Insertions
9:00 - 9:30Jesus "Tito" Gonzalez, Vertex
Cell-Based Optical Approaches for Ion Channels and Modulators
9:30 - 10:00Douglass Krafte, Icagen
Identification of Ion Channel Modulators Across Gene Families
10:00 - 10:30Coffee Break
10:30 - 11:00Todd Holmes, New York University
Transgenic Expression of Modified Ion Channels to Probe Neural Circuits and Behavior
11:00 - 11:30Michael Kaleko, Genetic Therapy, Inc.
Application of Gene Transfer to the Investigation and Therapy of Channelopathies
11:30 - 12:30Summary and Discussion
Lead: Jeffrey Noebels, Baylor College of Medicine
Pathophysiological Mechanisms on Channelopathies
Discussants:Kenneth Weiss, Pennsylvania State University
Karen Ketchum, Celera
Angie Ribera, University of Colorado
OrganizersYuan Liu, NINDS
Randy Stewart, NINDS
Meenaxi Hiremath, NINDS
1:00 - 2:00Lunch


Last Modified April 8, 2011