Ball-and-Chain Inactivation in Potassium Channels

Abstract

Carefully orchestrated opening and closing of ion channels controls the diffusion of ions across cell membranes, generating the electrical signals required for fast transmission of information throughout the nervous system. Inactivation is a parsimonious means for channels to restrict ion conduction without the need to remove the activating stimulus. Voltage-gated channel inactivation plays crucial physiological roles, such as controlling action potential duration and firing frequency in neurons. The ball-and-chain moniker applies to a type of inactivation proposed first for sodium channels and later shown to be a universal mechanism. Still, structural evidence for this mechanism remained elusive until recently. We review the ball-and-chain inactivation research starting from its introduction as a crucial component of sodium conductance during electrical signaling in the classical Hodgkin and Huxley studies, through the discovery of its simple intuitive mechanism in potassium channels during the molecular cloning era, to the eventual elucidation of a potassium channel structure in a ball-and-chain inactivated state. Expected final online publication date for the Annual Review of Biophysics, Volume 52 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Two epilepsy‐associated variants in KCNA2 (KV1.2) at position H310 oppositely affect channel functional expression

“…a spontaneous reduction in current following channel opening, in turn shaping neuronal action potentials and modulating synaptic transmission (Cho et al., 2020). K V β1 subunits bound to cytosolic N‐terminal regions of K V 1 channels mediated channel inactivation by a ‘ball‐and‐chain’ mechanism (Sukomon et al., 2023): a part of K V β1, the ‘ball peptide’, is connected to the rest of the protein via a flexible ‘chain’ region. The ball peptide is thought to bind to the open channel pore, occluding it and preventing ionic flow.…”

Arbuscular mycorrhizal fungusRhizophagus irregularisexpresses an outwardly Shaker-like channel involved in rice potassium nutrition

“…It is however interesting to note that the RiSKC3 regions present upstream of S1 and downstream of S6, both of which have been shown to be present on the cytosolic face of the membrane in Shaker channels (29), do not display any of the functional domain presently identified in K + channels from the Shaker superfamily, such as the so-called ball-and-chain domain (B in Fig. 3A) and the Tetramerization domain (31, 32) (T1 in Fig.3A) identified in DmShB, the cyclic-nucleotide-binding (homology) domain (CNBD in Fig. 3A) identified in HsKcnh1 (26) and in AtSKOR (28) or the ankyrin domain (ANKY in Fig.…”

“…3B), which can be assumed to confer the role of voltage-sensor to this segment, and the so-called pore-forming region, between the 5 th and the 6 th transmembrane segments, harboring the hallmark motif GYGD of K + selective channels. It is worth to note that the regions upstream and downstream of the transmembrane hydrophobic core in RiSKC3 do not display any of the typical domains identified in animal or plant Shaker channels and shown to play a role in regulation of channel properties, such as the ball-and-chain domain and the tetramerization domain found in Drosophila Shaker channels (31), or the CNBD found in some animal K + channels like the human HsKcnh1 (26, 36) and in all plant channels from the Shaker-like family (21, 34), or the ankyrin domain present in many plant Shaker channels (20) (Fig. 3).…”

Computational methods for unlocking the secrets of potassium channels: Structure, mechanism, and drug design

“…[106][107][108][109] Calcium-dependent inactivation in calciumactivated channels (like MthK channel) is triggered by increased intracellular calcium, causing structural changes, and is crucial for channels linked to cellular excitability. [110][111][112][113] Additionally, voltage-gated channels undergo voltagedependent inactivation in response to changes in membrane potential, important for controlling action potentials. 114,115 These mechanisms, which vary in response to internal and external factors, are pivotal for K + channels' roles in cellular signaling and homeostasis.…”

“…N‐type, also called as “ball‐and‐chain” inactivation, can quickly block the opened channel, suitable for rapid responses, while C‐type inactivation, relatively slower in nature, can prevent ion passage through the changes and is caused by the shrinkage or collapse of the SF region 106–109 . Calcium‐dependent inactivation in calcium‐activated channels (like MthK channel) is triggered by increased intracellular calcium, causing structural changes, and is crucial for channels linked to cellular excitability 110–113 . Additionally, voltage‐gated channels undergo voltage‐dependent inactivation in response to changes in membrane potential, important for controlling action potentials 114,115 .…”