Cardiac rhythm is triggered and maintained by synchronized electrical impulses throughout the heart. The slow delayed rectifier current, IKs, plays a vital role in shaping the repolarization phase of human cardiac action potentials, which are ∼250–350 ms long. The molecular constituent of IKs is a channel complex formed by KCNQ1 (Kv7.1 or KvLQT1) in association with KCNE1 (minK). KCNQ1 belongs to the voltage-gated potassium channel superfamily and is the pore-forming subunit of IKs channels. Mutations in the kcnq1 gene are associated with several congenital cardiac diseases, including long QT syndromes, familial atrial fibrillation, and short QT syndromes. In the United States, 3,000–4,000 cases of sudden death in children and young adults occur each year associated with inherited long QT syndrome; ∼40% of these are due to loss-of-function mutations in the kcnq1 gene. In addition to their role in the human heart, KCNQ1 channels are also essential for the function of epithelial cells in various organs, including colon, kidney, inner ear, and small intestine. We aim to understand the activation and regulation mechanisms of KCNQ1 to guide pharmaceutical modulation.
Structure of KCNQ1-CaM complex provides insights to long-QT syndromes
KCNQ1 is the pore-forming subunit of cardiac slow-delayed rectifier potassium (IKs) channels. Mutations in the kcnq1 gene are the leading cause of congenital long QT syndrome (LQTS). During the postdoc training in the Mackinnon lab, Dr. Sun reported the first cryo-EM structure of the KCNQ1-CaM complex. The conformation corresponds to an “uncoupled,” PIP2-free state of KCNQ1, with activated voltage sensors and a closed pore. Unique structural features within the S4-S5 linker permit uncoupling of the voltage sensor from the pore in the absence of PIP2. CaM contacts the KCNQ1 voltage sensor through a specific interface involving a residue on CaM that is mutated in a form of inherited LQTS, providing new insights into the pathogenesis of generic long-QT syndromes.
Structural basis of human KCNQ1 modulation and activation
Functional properties of KCNQ1 are regulated in a tissue-specific manner through co-assembly with beta subunits KCNE1-5. In non-excitable cells, KCNQ1 forms a complex with KCNE3, which suppresses channel closure at negative membrane voltages that otherwise would close it. Pore opening is regulated by the signaling lipid PIP2. Using cryo-EM, we show that KCNE3 tucks its single-membrane-spanning helix against KCNQ1, at a location that appears to lock the voltage sensor in its depolarized conformation. Without PIP2, the pore remains closed. Upon addition, PIP2 occupies a site on KCNQ1 within the inner membrane leaflet, which triggers a large conformational change that leads to the dilation of the pore's gate. It is likely that this mechanism of PIP2 activation is conserved among KCNQ channels.