Thursday, November 21, 2024
11/21/2024
Project Summary (Abstract): The proposed work seeks to identify the molecular basis for a novel interaction between two proteins that are typically found in electrically active cells such as neurons and cardiac muscles cells. One of the proteins is known as a voltage-dependent, potassium-selective KV7.1 channel. This protein, hereafter KV7.1, is a major player for the termination of fast electrical signals. For instance, KV7.1 is critical for terminating each cycle of the rhythmic electrical signaling in the heart. In fact, a faulty, low-performing KV7.1 leads to arrhythmias that, in some cases, can unchain fibrillations that result in death. In the auditory system, such alterations lead to hearing disorders and deafness. The second protein is known as NaVβ1. This is an auxiliary subunit that regulates the activity of sodium-selective, voltage-dependent (NaV) channels which are responsible for initiating fast electrical signals. NaVβ1 is an important positive regulator of NaV channels. In a few words, NaV starts an electrical signal event, and KV7.1 contributes to its termination. What is novel here is that NaVβ1 not only boosts the activity of NaV channels, but also decreases the activity of KV7.1 as we have recently found. Furthermore, we found that a fourth protein, KCNE1 can protect KV7.1 from the inhibitory action of NaVβ1. Like with the pair NaVβ1-NaV channel, KCNE1 can increase the activity and expression of KV7.1 channels. In cells that express these four proteins, we will find NaV channels associated with NaVβ1 and KV7.1 channels associated with KCNE1. In the absence of KCNE1, our recent data suggest that, while boosting that of NaV channels, NaVβ1 will decrease KV7.1 activity. In this case, the ON-OFF balance of events generating fast electrical signals will be altered, leading to abnormal electrical events. Our novel finding constitutes a shift in our understanding of how mutations in KCNE1 can affect cellular electrical signaling. If KCNE1 is mutated, KV7.1 activity could be lower due to such mutation, but also could be further decreased by the action of NaVβ1. Some mutations in KCNE1 have been shown to cause little alteration in the activity of the KCNE1/KV7.1 complex when compared with the non-mutated pair. Yet such mutations are linked to diseases. This apparent disconnect may emerge from not considering the action of NaVβ1, which could have been gone undetected. This proposal aims at addressing this issue by expanding our understanding of the effect of mutations in KCNE1 in term of its ability to shield KV7.1 from the action of NaVβ1. The outcomes of this work will provide a novel paradigm in which KCNE1 is not only a positive modulator of KV7.1 channels, but also a molecular shield protecting these channels from the action of other regulatory subunits.
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