3D Structures and Molecular Evolution of Ion Channels

Abstract

Ion channels mediate selective passive transport of ions across biomembranes. They participate in diverse physiological processes and belong to distinct protein families. Understanding specific roles of different channels in physiology, pathology, and pharmacology requires knowledge of their origin and evolution. Traditional approaches include experimental physiological studies and analysis of sequences and genomes. In the last two decades, availability of 3D structures of many ion channel proteins revolutionized ion channel studies, including their evolution. In this chapter, we consider examples of how 3D structures provided clues for understanding evolutionary aspects of multi-domain organization, domain folding, and roles of highly conserved and variable residues. Such achievements are important for addressing practical problems including drug design, channelopathies, and acquired resistance to insecticides.

The fallacy of functional nomenclature in the kingdom of biological multifunctionality: physiological and evolutionary considerations on ion channels

“…The ability to perform multiple jobs is also reported for the 'ligand-gated ion channels' , a term referring to the J Physiol 602.11 large family of ion channels that are gated by extracellular ligands (Anderson & Greenberg, 2001;Tikhonov & Zhorov, 2018;Jaiteh et al, 2016); nonetheless, the same proteins are defined as 'ionotropic receptors' to emphasize their intrinsic ability to act as receptors which, upon ligand binding, directly promote membrane currents. These are two annotations (receptors/ion channels) for the same biological structures of paramount relevance, because they include widespread and conserved membrane transducers for the bioactivity of neurotransmitters such as acetylcholine, glutamate, γ -aminobutyric acid (GABA) and others, in addition to purines, including extracellular ATP (P2X purinergic receptors).…”

“…Their long evolutionary history, which originated in the very first prokaryotic forms of life and expanded into distinct structural and functional classes during metazoan evolution, resulted in a combination of conserved traits and the creation of a great diversity. In addition, their modular organization underwent recombinations and remodelling of protein domains, which sometimes originated from evolutionarily distant protein families (Anderson & Greenberg, 2001; Tikhonov & Zhorov, 2018; Coyote‐Maestas et al., 2021; Himmel & Cox, 2020; Jaiteh et al., 2016; Moran et al., 2015; Okamura et al., 2005).…”

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

“…17 Different types of K + channels usually have different regulatory domains and can be regulated by various stimuli. 7 To understand the complex function of K + channels, structural biologists try to resolve their three-dimensional (3D) structures based on experimental methods, 18,19 such as x-ray crystallography (x-ray), nuclear magnetic resonance spectroscopy (NMR), and cryo-electron microscopy (Cryo-EM). Although these methods can obtain relatively precise 3D structures, it requires expensive equipment and skilled technicians.…”

Ion Selectivity and Permeation Mechanism in a Cyclodextrin-Based Channel

“…2 Since ion channels have such an important role in the functioning of cells, there have been numerous studies to decipher the structure of these channels, with an objective to better understand ion transport. 3 Biological ion channels have inspired the design of synthetic ion channels, which have promising applications in several areas of medicine and materials science. Potential applications include the use of crown ether-based channels to disrupt homeostasis in pathogenic bacteria, the use of "artificial β-barrels" in sensing and catalysis, the use of channels with π-stacked architectures as artificial photosystems, and the use of channels with metal− organic scaffolds for the absorption of hydrogen and carbon dioxide.…”

“…Malfunctioning of ion channels as a result of mutations can lead to a number of diseases . Since ion channels have such an important role in the functioning of cells, there have been numerous studies to decipher the structure of these channels, with an objective to better understand ion transport . Biological ion channels have inspired the design of synthetic ion channels, which have promising applications in several areas of medicine and materials science.…”