RT Journal Article
SR Electronic
T1 Isoform-selective KCNA1 potassium channel openers built from glycine
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.119.264507
DO 10.1124/jpet.119.264507
A1 Rian W Manville
A1 Geoffrey W Abbott
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/03/26/jpet.119.264507.abstract
AB 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 (Kv1.1), an archetypal Shaker-type Kv channel, loss-of-function mutations in which cause Episodic Ataxia Type 1 (EA1). EA1 causes constant myokomia, episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) 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.SIGNIFICANCE STATEMENT Inherited loss-of-function gene sequence variants in KCNA1, which encodes the KCNA1 (Kv1.1) voltage-gated potassium channel, cause Episodic Ataxia Type 1 (EA1) - a movement disorder also linked to epilepsy and developmental delay. We have discovered several isoform-specific KCNA1-activating small molecules, addressing a notable gap in the field and providing possible lead compounds and a novel chemical space for the development of potential future therapeutic drugs for EA1.