Requirement of a Macromolecular Signaling Complex for β Adrenergic Receptor Modulation of the KCNQ1-KCNE1 Potassium Channel

TLDR

β‑adrenergic receptor activation shortens cardiac action potential duration by increasing the slow outward potassium current, and mutations in the I KS channel subunits hKCNQ1 and hKCNE1 prolong APD, causing long‑QT syndrome. β‑adrenergic modulation of the I KS current depends on a macromolecular complex that tethers PKA and PP1 to hKCNQ1 via the yotiao protein, whose leucine‑zipper binding is disrupted by the LQTS mutation G589D, revealing the mechanism by which sympathetic signaling regulates cardiac action potential duration.

Abstract

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by β adrenergic receptor (βAR) activation, which increases the slow outward potassium ion current ( I KS ). Mutations in two human I KS channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that βAR modulation of I KS requires targeting of adenosine 3′,5′-monophosphate (cAMP)–dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through I KS .