Numerous neurodegenerative diseases result from altered ion channel function and mutations. The intracellular redox status can significantly alter the gating characteristics of ion channels. Abundant neurodegenerative diseases associated with oxidative stress have been documented, including Parkinson’s, Alzheimer’s, spinocerebellar ataxia, amyotrophic lateral sclerosis, and Huntington’s disease. Reactive oxygen and nitrogen species compounds trigger posttranslational alterations that target specific sites within the subunits responsible for channel assembly. These alterations include the adjustment of cysteine residues through redox reactions induced by reactive oxygen species (ROS), nitration, and S-nitrosylation assisted by nitric oxide of tyrosine residues through peroxynitrite. Several ion channels have been directly investigated for their functional responses to oxidizing agents and oxidative stress. This review primarily explores the relationship and potential links between oxidative stress and ion channels in neurodegenerative conditions, such as cerebellar ataxias and Parkinson’s disease. The potential correlation between oxidative stress and ion channels could hold promise for developing innovative therapies for common neurodegenerative diseases.

Small-conductance Ca²⁺-activated K⁺ (K_Ca2.1-K_Ca2.3) channels modulate neuronal and cardiac excitability. We report cryo-electron microscopy structures of the K_Ca2.2 channel in complex with calmodulin and Ca²⁺, alone or bound to two small molecule inhibitors, at 3.18, 3.50, 2.99 and 2.97 angstrom resolution, respectively. Extracellular S3-S4 loops in β-hairpin configuration form an outer canopy over the pore with an aromatic box at the canopy’s center. Each S3-S4 β-hairpin is tethered to the selectivity filter in the neighboring subunit by inter-subunit hydrogen bonds. This hydrogen bond network flips the aromatic residue (Tyr362) in the filter’s GYG signature by 180°, causing the outer selectivity filter to widen and water to enter the filter. Disruption of the tether by a mutation narrows the outer selectivity filter, realigns Tyr362 to the position seen in other K⁺ channels, and significantly increases unitary conductance. UCL1684, a mimetic of the bee venom peptide apamin, sits atop the canopy and occludes the opening in the aromatic box. AP14145, an analogue of a therapeutic for atrial fibrillation, binds in the central cavity below the selectivity filter and induces closure of the inner gate. These structures provide a basis for understanding the small unitary conductance and pharmacology of K_Ca2.x channels.

Redox regulation is crucial for the cardiac action potential, coordinating the sodium-driven depolarization, calcium-mediated plateau formation, and potassium-dependent repolarization processes required for proper heart function. Under physiological conditions, low-level reactive oxygen species (ROS), generated by mitochondria and membrane oxidases, adjust ion channel function and support excitation–contraction coupling. However, when ROS accumulate, they modify a variety of important channel proteins in cardiomyocytes, which commonly results in reducing potassium currents, enhancing sodium and calcium influx, and enhancing intracellular calcium release. These redox-driven alterations disrupt the cardiac rhythm, promote after-depolarizations, impair contractile force, and accelerate the development of heart diseases. Experimental models demonstrate that oxidizing agents reduce repolarizing currents, whereas reducing systems restore normal channel activity. Similarly, oxidative modifications of calcium-handling proteins amplify sarcoplasmic reticulum release and diastolic calcium leak. Understanding the precise redox-dependent modifications of cardiac ion channels would guide new possibilities for targeted therapies aimed at restoring electrophysiological homeostasis under oxidative stress, potentially alleviating myocardial infarction and cardiovascular dysfunction.

K⁺ channels are involved in many critical functions in lung physiology. Recently, the family of Ca²⁺-activated K⁺ channels (K_Ca) has received more attention, and a massive amount of effort has been devoted to developing selective medications targeting these channels. Within the family of K_Ca channels, three small-conductance Ca²⁺-activated K⁺ (K_Ca2) channel subtypes, together with the intermediate-conductance K_Ca3.1 channel, are voltage-independent K⁺ channels, and they mediate Ca²⁺-induced membrane hyperpolarization. Many K_Ca2 channel members are involved in crucial roles in physiological and pathological systems throughout the body. In this article, different subtypes of K_Ca2 and K_Ca3.1 channels and their functions in respiratory diseases are discussed. Additionally, the pharmacology of the K_Ca2 and K_Ca3.1 channels and the link between these channels and respiratory ciliary regulations will be explained in more detail. In the future, specific modulators for small or intermediate Ca²⁺-activated K⁺ channels may offer a unique therapeutic opportunity to treat muco-obstructive lung diseases.

Small-conductance (K_Ca2.2) and intermediate-conductance (K_Ca3.1) Ca²⁺-activated K⁺ channels are gated by a Ca²⁺-calmodulin dependent mechanism. NS309 potentiates the activity of both K_Ca2.2 and K_Ca3.1, while rimtuzalcap selectively activates K_Ca2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound K_Ca2.2 and K_Ca3.1, in addition to structures of rimtuzalcap-bound K_Ca2.2 and mutant K_Ca3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K_Ca2.2. NS309 binds to pre-existing pockets in both channels, while the bulkier rimtuzalcap binds in an induced-fit pocket in K_Ca2.2 requiring conformational changes. In K_Ca2.2, calmodulin’s N-lobes are sufficiently far apart to enable conformational changes to accommodate either NS309 or rimtuzalcap. In K_Ca3.1, calmodulin’s N-lobes are closer to each other and constrained by K_Ca3.1’s HC helices, which allows binding of NS309 but not rimtuzalcap. Replacement of arginine-355 in K_Ca3.1’s HB helix with lysine (K_Ca3.1_R355K) allows the binding of rimtuzalcap and renders the mutant channel sensitive to rimtuzalcap. These structures provide a framework for structure-based drug design targeting K_Ca2.2 channels.

Small-conductance (K _Ca 2.2) and intermediate-conductance (K _Ca 3.1) Ca ²⁺ -activated K ⁺ channels are gated by a Ca ²⁺ -calmodulin dependent mechanism. NS309 potentiates the activity of both K _Ca 2.2 and K _Ca 3.1, while rimtuzalcap selectively activates K _Ca 2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of K _Ca 2.2 channels bound with NS309 and rimtuzalcap, in addition to K _Ca 3.1 channels with NS309. The different conformations of calmodulin and the cytoplasmic HC helices in the two channels underlie the subtype-selectivity of rimtuzalcap for K _Ca 2.2. Calmodulin’s N-lobes in the K _Ca 2.2 structure are far apart and undergo conformational changes to accommodate either NS309 or rimtuzalcap. Calmodulin’s N-lobes in the K _Ca 3.1 structure are closer to each other and are constrained by the HC helices of K _Ca 3.1, which allows binding of NS309 but not of the bulkier rimtuzalcap. These structures provide a framework for structure-based drug design targeting K _Ca 2.2 channels.