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

Victoria A. Baronas, Runying Y. Yang, Luis Carlos Morales, Simonetta Sipione and Harley T. Kurata ()
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Victoria A. Baronas: University of Alberta
Runying Y. Yang: University of Alberta
Luis Carlos Morales: University of Alberta
Simonetta Sipione: University of Alberta
Harley T. Kurata: University of Alberta

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06859-x

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