notch signaling pathway LQT can have numerous clinical
LQT1 can have numerous clinical manifestations, ranging from no symptoms to sudden cardiac death, which reflects the heterogeneity in channel dysfunction. Mutation type, location, and even a patient׳s ethnic background, age, and gender are critical factors that affect the pathophysiology of the disease . A variety of studies have shown that LQT1 is more frequently triggered by adrenergic stimuli (e.g., physical exertion or emotional stress) compared with other forms of LQTS, particularly by diving and swimming [20–22]. Under normal physiological conditions, sympathetic activation promotes IKs, which shortens ventricular repolarization against the activation of L-type Ca2+ current and thereby protects against Ca2+-related arrhythmogenicity . When IKs is defective because of a KCNQ1 mutation, the ventricular repolarization or QT interval fails to shorten appropriately, thus creating a highly arrhythmogenic condition .
Molecular basis of LQT1 The LQT1-related KCNQ1 gene is 404kb long and located on chromosome 11p15.5. This gene codes for a 75-kDa protein containing 676 amino acids [11,23] and is mainly expressed in the heart, kidneys, small intestine, pancreas, prostate, and other non-excitable epithelial tissues . It belongs to the Kv7 subfamily of voltage-gated K+ channels (Kv) and shares a tetrameric architecture with all Kv channels. Each subunit contains six membrane-spanning segments (S1–S6 involving amino notch signaling pathway residues 122–348) connected by alternating intra- and extra-cellular loops, as well as a pore loop (amino acid residues 300–320) located between segments S5 and S6, with a cytosolic amino terminus (NH2 terminus, residues 1–121) and a long cytosolic carboxyl terminus (COOH terminus, residues 349 to 676) (Fig. 1) [19,25,26]. The four subunits form a symmetrical alignment for the channel molecule together with KCNE1 (protein containing 129 amino acids with a single transmembrane segment) and Yotiao proteins, and construct a specialized pathway that allows for the conduction of potassium ions through water-filled pores located in the center of the complex. S1-S4 segments of the potassium channel form a voltage-sensing domain (VSD). The S4 helix of KCNQ1 consists of a peculiar sequence of positively charged amino acids forming a region that is involved in sensing the membrane voltage and controlling the open probability of the channel . In the resting state of the channel, these positively charged side chains are expected to be closer to the intracellular side of the membrane. Upon depolarization, effective charge motion within the membrane electric field toward the extracellular side of the membrane is accomplished through a series of conformational changes in the VSDs that lead to opening of the channel . The pore region is composed of two transmembrane segments (S5 and S6) joined together by a linker (including a pore loop) that contains the conserved amino acids of the selectivity filter (residues 312–317) and affects the channel current amplitude, selectivity among ions, and channel blockade [29,30]. KCNQ1 possesses a large COOH terminus that is important for channel gating, assembly, and trafficking [19,31]. The COOH terminus is comprised of four amphipathic α-helices, coiled-coils, and clusters of basic amino acids. A and B proximal helices form sites for calmodulin (CaM) binding, whereas the distal coiled-coil helix C and helix D are responsible for tetramerization [19,31]. Helix C interacts with the KCNE1 distal COOH terminus and is thought to be a crucial region for modulation by phosphatidylinositol-4,5-bisphosphate (PIP2), which acts to stabilize the open state of the channel . A domain near the COOH terminus (residues 589–620) of KCNQ1 is responsible for subunit assembly specificity, and deletion of a part of this domain leads to impaired assembly of the channel complexes, followed by mistrafficking . In the COOH terminus tail, a leucine zipper motif (residues 588–616) has been identified as the unique site through which A-kinase anchoring protein 9 (AKAP9, or Yotiao) targets protein kinase A (PKA) and protein phosphatase 1 (PP1) to the KCNQ1 complex . Although the NH2 terminus is relatively short, it contains an important residue (S27) that is critical for mediating the phosphorylation of KCNQ1 .