The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases

Abstract

Introduction KCa2 or small-conductance Ca2+-activated K+ channels (SK) are expressed in many areas of the central nervous system where they participate in the regulation of neuronal afterhyperpolarization and excitability, and also serve as negative feedback regulators on the glutamate -NMDA pathway. Areas covered This review focuses on the role of KCa2 channels in learning and memory and their potential as therapeutic targets for Alzheimer’s and Parkinson’s disease, ataxia, schizophrenia, and alcohol dependence. Expert opinion There currently exists relatively solid evidence supporting the use of KCa2 activators for ataxia. Genetic KCa2 channel suppression in deep cerebellar neurons induces ataxia, while KCa2 activators like 1-EBIO, SKA-31 and NS13001 improve motor deficits in mouse models of episodic ataxia (EA) and spinal cerebellar ataxia (SCA). Use of KCa2 activators for ataxia is further supported by a report that riluzole improves ataxia in a small clinical trial. Based on accumulating literature evidence, KCa2 activators further appear attractive for the treatment of alcohol dependence and withdrawal. Regarding Alzheimer’s disease, Parkinson’s and schizophrenia further research, including long-term studies in disease relevant animal models, will be needed to determine whether KCa2 channels constitute valid targets and whether activators or inhibitors would be needed to positively affect disease outcomes.

International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels

“…Based on the physiologic role of K Ca 2 channels in regulating neuronal excitability, K Ca 2 activators, which can reduce neuronal firing, are being investigated for the treatment of conditions characterized by hyperexcitability, such epilepsy, ataxia, and alcohol dependence (Lam et al, 2013). K Ca 2 channel inhibitors in contrast have been suggested to improve learning and memory (Lam et al, 2013) and are being investigated preclinically for the treatment of atrial fibrillation based on the role of K Ca 2 channels in modulating action potential duration in the heart (Grunnet et al, 2012).…”

“…K Ca 2 channel inhibitors in contrast have been suggested to improve learning and memory (Lam et al, 2013) and are being investigated preclinically for the treatment of atrial fibrillation based on the role of K Ca 2 channels in modulating action potential duration in the heart (Grunnet et al, 2012).…”

Neurodegeneration in the elderly – When the blood type matters: An overview of the McLeod syndrome with focus on hematological features

“…Gardos channels are ubiquitously expressed in body tissue 79 and their functionality may depend on intact XK protein. In line with this assumption, disruption of XK may therefore lead to multisystem deficiencies by impairment of Gardos functionality which could explain the chef affected cardiac and neuronal tissues in MLS [79][80][81][82][83] (see Table 1). …”

Functional and Molecular Diversity of Native Neuronal K + Channels

“…acquired neurological diseases, and these changes contribute to developmental, movement, behavioral, intellectual and seizure disorders (Singh et al, 2006;Barcia et al, 2012;Duarri et al, 2012;Lee et al, 2012Lee et al, , 2014bLam et al, 2013;Kim and Kaczmarek, 2014;Aidi-Knani et al, 2015). See also: The Genetics of Neuronal Channelopathies Rapidly activating and inactivating A-type K + currents (I A ), for example, are key determinants of excitability in a variety of mammalian peripheral and central neuronal cell types (Johnston et al, 2000;Nerbonne, 2000, 2001;Kim et al, 2005;Phuket and Covarrubias, 2009;Carrasquillo et al, 2012;Yunoki et al, 2014).…”