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(Circulation Research. 2000;86:367.)
© 2000 American Heart Association, Inc.

Editorials

Anchors Aweigh!

Ion Channels, Cytoskeletal Proteins, and Cellular Excitability

Paul B. Bennett

From Merck Research Laboratories, West Point, Pa.

Correspondence to Paul Bennett, PhD, Senior Director Ion Channel Pharmacology, WP 26-265, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486. E-mail paul_bennett@merck.com

Key Words: Na⁺ channel • long-QT syndrome • antiarrhythmic agent • molecular biology • genetics

	Introduction

 
Genomics, proteomics, transgenics, molecular medicine: these are some of the scientific catch phrases of the 1990s. The hard work and high expectations of the past decade are beginning to influence reality. Results have accrued to the point that we can begin applying molecular knowledge to therapeutics. Although still in the formative stages, one cannot help but see the vast potential of the exponentially growing molecular knowledge base for understanding physiology and pathophysiology.

	Ion Channel Disorders

 
In recent years, increasing numbers of ion channelopathies—disorders involving mutations in ion channel genes—have been recognized. These disorders include periodic paralyzes, migraine, ataxias, epilepsy, and cardiac arrhythmias to name a few. Research efforts have been directed toward identifying the candidate ion channel genes and their mutations and understanding the functional consequences of these mutations. In many cases, the results have been highly rewarding with a biophysical phenotype that easily correlates with the ultimate clinical phenotype.¹ There are also cases where mutations in channel proteins, all of which are known to lead to a clinical disorder, do not have, as yet, a phenotype that is consistent with an interpretable hypothesis. For example, in familial hemiplegic migraine, individual mutations in a Ca²⁺ channel subunit gene can apparently cause either loss or gain of function, depending on the mutation.^{2 3 4 5 6} Perhaps different mutant channels behave differently in their native environment and when interacting with auxiliary proteins. Perhaps additional analysis will reveal a mechanism. Yet at present, it is challenging to reconcile this disparate behavior with the common clinical phenotype of migraine. Presumably, . . . [Full Text of this Article]

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