Isoform-selective KCNA1 potassium channel openers built from glycine

Rian Manville, Geoffrey Abbott

Research output: Contribution to journalArticle

Abstract

Loss of function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to isoform-selectively activate specific Kv channels. One example is KCNA1 Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1) (Kv1.1), an archetypal Shaker-type Kv channel, in which loss-of-function mutations cause episodic ataxia type 1 (EA1). EA1 causes constant myokomia and episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter γ-aminobutyric acid and modified versions of glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of fluorine atoms within the fluorophenyl ring of glycine derivatives produces isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1. The findings refine our understanding of the molecular basis for KCNQ versus KCNA1 activation and isoform selectivity and constitute, to our knowledge, the first reported isoform-selective KCNA1 opener.

Original languageEnglish
Pages (from-to)391-401
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume373
Issue number3
DOIs
Publication statusPublished - 13 May 2020

Keywords

  • drug design
  • drug discovery
  • ion channels
  • neuromuscular pharmacology
  • neurotransmitters
  • skeletal muscle
  • voltage-gated potassium channels

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