Slc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations

Nat Commun. 2018 Oct 24;9(1):4417. doi: 10.1038/s41467-018-06859-x.


Kv1.2 is a prominent voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. We explored multi-protein complexes containing Kv1.2 using mass spectrometry followed by screening for effects on Kv1.2. We report that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2. Co-expression with Slc7a5 reduces total Kv1.2 protein, and dramatically hyperpolarizes the voltage-dependence of activation by -47 mV. These effects are attenuated by expression of Slc3a2, a known binding partner of Slc7a5. The profound Slc7a5-mediated current suppression is partly explained by a combination of gating effects including accelerated inactivation and a hyperpolarizing shift of channel activation, causing channels to accumulate in a non-conducting state. Two recently reported Slc7a5 mutations linked to neurodevelopmental delay exhibit a localization defect and have attenuated effects on Kv1.2. In addition, epilepsy-linked gain-of-function Kv1.2 mutants exhibit enhanced sensitivity to Slc7a5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Electrophysiology
  • Epilepsy / genetics
  • Epilepsy / metabolism*
  • Flow Cytometry
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Kv1.2 Potassium Channel / genetics
  • Kv1.2 Potassium Channel / metabolism*
  • Large Neutral Amino Acid-Transporter 1 / genetics
  • Large Neutral Amino Acid-Transporter 1 / metabolism*
  • Mass Spectrometry
  • Mice
  • Rats, Sprague-Dawley


  • Kv1.2 Potassium Channel
  • Large Neutral Amino Acid-Transporter 1