@misc{10481/106799,
year = {2025},
month = {9},
url = {https://hdl.handle.net/10481/106799},
abstract = {Background/Objectives: The voltage-gated potassium channels of the Kv4 family (Kv4.1,
Kv4.2, Kv4.3) regulate neuronal excitability and synaptic integration. The dysregulation
of these channels has been linked to neurodegenerative diseases, such as Alzheimer’s
disease (AD), spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), prion diseases,
and Parkinson’s disease (PD). Current evidence is scattered across diverse models, and
a systematic synthesis is lacking. This review seeks to compile and analyze data on Kv4
channel alterations in neurodegeneration, focusing on genetic variants, functional changes,
and phenotypic consequences. Methods: A systematic search was conducted for peerreviewed studies, including human participants, human-derived cell models, and relevant
animal models. Studies were considered eligible if they investigated Kv4.1–Kv4.3 (encoded by gene encoding the Kv4.1-Kv4.3 α-subunit of voltage-gated A-type potassium
channels (KCND1-KCND3)) expression, function, or genetic variants, as well as associated
auxiliary subunits such as DPP6 (dipeptidyl peptidase–like protein 6) and KChIP2 (Kv
channel–interacting protein 2), in neurodegenerative diseases. Both observational and
experimental designs were considered. Data extraction included disease type, model, Kv4
subunit, functional or genetic findings, and key outcomes. Risk of bias was assessed in
all included studies. Results: Kv4 channels exhibit significant functional and expression
changes in various neurodegenerative diseases. In AD and prionopathies, reduced Kv4.1-
and Kv4.2-mediated currents contribute to neuronal hyperexcitability. In spinocerebellar
ataxias, KCND3 mutations cause loss- or gain-of-function phenotypes in Kv4.3, disrupting
cerebellar signaling. In models of ALS and PD, Kv4 dysfunction correlates with altered
neuronal excitability and can be modulated pharmacologically. Subunit modulators such
as DPP6 and KChIP2 influence channel function and could represent therapeutic targets.
Conclusions: Kv4 channels are crucial for neuronal excitability in multiple neurodegenerative contexts. Dysregulation through genetic or pathological mechanisms contributes to
functional deficits, highlighting Kv4 channels as promising targets for interventions aimed
at restoring electrical homeostasis and mitigating early neuronal dysfunction.},
organization = {Autonomous City of Ceuta (Ref. No. CE-10-UGR24)},
organization = {Universidad de Granada (PPJIA2022.09)},
publisher = {MDPI},
keywords = {neurodegeneration},
keywords = {Amyotrophic lateral sclerosis},
keywords = {Alzheimer’s disease},
keywords = {Parkinson’s disease},
title = {Systematic Review of the Role of Kv4.x Potassium Channels in Neurodegenerative Diseases: Implications for Neuronal Excitability and Therapeutic Modulation},
doi = {10.3390/physiologia5030031},
author = {Teruel Peña, Bárbara and Gómez-Torres, Piedad and Galarreta-Aperte, Sergio and Suleiman-Martos, Nora and Prieto, Isabel and Ramírez-Sánchez, Manuel and Fernández-Martos, Carmen M. and Domínguez-Vías, Germán},
}