Potassium Channels: A Potential Therapeutic Target for Parkinson’s Disease

Abstract

The pathogenesis of the second major neurodegenerative disorder, Parkinson's disease (PD), is closely associated with the dysfunction of potassium (K) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K channels enhances the spontaneous firing frequency of nigral dopamine (DA) neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum. Recently, three K channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance (SK) channels, A-type K channels, and K7/KCNQ channels. In this review, we summarize the physiological and pharmacological effects of the three K channels. We also describe in detail the laboratory investigations regarding K channels as a potential therapeutic target for PD.

A new multigene HCIQ subfamily from the sea anemone Heteractis crispa encodes Kunitz-peptides exhibiting neuroprotective activity against 6-hydroxydopamine

“…The authors hypothesized the effect is caused by blocking K v 1 channels 31 . Indeed, K v channels are actively involved in the regulation of neuronal processes and considered potential therapeutic targets for some neurodegenerative diseases, such as PD 59,60 . Thus, 4-aminopyridine, the blocker of K v 1 and K v 3 channel subfamily, suppresses MPTP-induced neurodegeneration and rat behavioral disturbances 61 ; ShK-170 from S. helianthus is able to mitigate radiation-induced brain injury via K v 1.3 blocking 62 .…”

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

“…Pathogenesis of Parkinson’s disease (PD), which is associated to death of DA neurons in the SNc ( Surmeier et al, 2010 ) has been also related to K + channels dysfunction, including SK channels ( Wang et al, 2008 ; Chen et al, 2018 ). This hypothesis is consistent with the observed roles of SK channels as regulators of dopaminergic neurotransmission in the SNc, protecting DA neurons from excitotoxic death (as reviewed in the previous section; see also Dolga et al, 2014 ).…”

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5

“…To date, various kinds of Kv1.5 modulators have been disclosed, herein, we summarize the molecular structures and functionality of different types of Kv1.5 modulators with their chemical structure as follows (Table 1, Figure 2). As shown in Table 1, the existing Kv1.5 modulators can be divided into four categories: clinical cardiovascular drugs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), other clinical drugs (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), drugs in development (29)(30)(31)(32)(33)(34)(35)(36)(37), and natural products (38)(39)(40)(41)(42)(43)(44)(45)(4...…”

“…As for other clinical drugs, CNS agents include: donepezil (15), which is generally used as an anti-Alzheimer's agent; paroxetine (16), fluoxetine (17), and sertraline (18), which are usually used as antidepressant agents; and bupivacaine (23), propofol (24), midazolam (25), tolbutamide (26), and benzocaine (27), which are utilized as anesthetic agents. hERGs (human ether-à-go-go-related genes) are widely associated with CNS diseases [16][17][18], thus it is not strange that active CNS agents can effectively modulate Kv1.5 according to the homology of the protein. Especially the neurotransmitter acetylcholine, which is an important substance that modulates the acetylcholine-activated K + current [19], however, only the piperidine type acetylcholine inhibitor donepezil showed significant inhibitory effect on Kv1.5, the same phenomenon was not present in another inhibitor tacrine [15], suggesting the selectivity of the binding site of Kv1.5.…”