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Principal Investigator: Carlos Alberto Villalba-Galea
Organization: UNIVERSITY OF THE PACIFIC-STOCKTON
Fiscal Year: 2024
Award: $168,750
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Address><Affect><Amino Acids><Aminoacetic Acid><Architecture><Arrhythmia><Auditory system><Brain><Brain Nervous System><Cardiac Arrhythmia><Cardiac Muscle Cells><Cardiac Myocytes><Cardiocyte><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><Cessation of life><Characteristics><Clinical><Complex><Cyclicity><Cytoplasmic Membrane><Data><Death><Dependence><Disease><Disorder><Encephalon><Encephalopathies><Engineering><Engineering / Architecture><Equilibrium><Ethers><Event><Exposure to><Family><Family member><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glycine><Hearing Disorders><Hearing problem><Heart><Heart Arrhythmias><Heart Muscle Cells><Heart myocyte><Human><Intracellular Communication and Signaling><Isoforms><K element><Kinetics><Lead><Leucine><Link><Literature><Membrane><Membrane Potentials><Modeling><Modern Man><Modification><Molecular><Muscle Cells><Mutate><Mutation><Myocytes><Na element><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nonsense Mutation><Oocytes><Organ><Outcome><Ovocytes><Pb element><Periodicity><Plasma Membrane><Potassium><Predisposition><Process><Protein Isoforms><Proteins><RNA Splicing><Recovery><Resting Potentials><Rhythmicity><Signal Transduction><Signal Transduction Systems><Signaling><Sodium><Splicing><Susceptibility><TM Domain><Testing><Transmembrane Domain><Transmembrane Potentials><Transmembrane Region><Ventricular><Work><Xenopus oocyte><amino group><aminoacid><auditory disease><auditory disorder><auditory dysfunction><auditory problem><balance><balance function><biological signal transduction><cardiomyocyte><cell type><deafness><disease causing variant><disease-causing mutation><extracellular><genome mutation><hearing disease><heavy metal Pb><heavy metal lead><membrane structure><neuronal><non-sense mutation><novel><pathogenic variant><plasmalemma><prevent><preventing><virtual><voltage>