Diversity of ion channels

In 1951 Paul Fatt and Bernard Katz contemplated the following question regarding the generation of end-plate potentials: “The question arises how such a large flux of ions can be maintained across the presumably minute area of the motor end-plate . ”. While they did not have an answer at that time, they suggested that “. small quantities of acetylcholine alter the end-plate surface in such a way that other ions can be rapidly transferred across it . we must think in terms of some chemical breakdown of a local ion barrier which occurs as soon as acetylcholine combines with it . ” (Fatt & Katz 1951) and in a review 4 years later del Castillo and Katz suggested that “. ACh may ‘short-circuit’ the membrane, i.e. create aqueous channels through which small ions can pass . ” (del Castillo & Katz 1956). Experimental evidence demonstrating the existence of single channels emerged roughly two decades later when Erwin Neher and Bert Sakmann used their newly invented patch-clamp technique to show current flow through single ion channels (Neher et al. 1978). Another 20 years later, Roderick MacKinnon and his colleagues provided the first three-dimensional molecular structure of an ion channel (MacKinnon et al. 1998). The history of ion channels is marked by trailblazing theoretical and experimental research that triggered conceptual leaps in our understanding of cellular excitability and led to significant technological developments. In the last few decades, we have continued to see the explosion of ground-breaking developments in research that focuses on ion channels’ structure and function. It is widely known that ion channels mediate the transport of specific ions across biological membranes. They evolved to be selective for the ions that permeate them and the molecules or conditions that activate them. The origin of many ion channels can be traced to periods preceding the development of the nervous system or even the emergence of animal multicellular organisms (Chiu et al. 1999, Burkhardt et al. 2011, Liebeskind et al. 2011). Ligand-gated ion channels that sense neurotransmitters in synapses are critical parts of the neuronal code. While the number of neurotransmitters is rather limited, the receptors sensing them show amazing functional and structural diversity. This diversity stems from the emergence of various subgroups within ion channel families, the assembly of various subunits in a combinatorial fashion and the large number of auxiliary proteins that interact with them. Recent technical advances have allowed the direct monitoring of channel mobility in the membrane, the detailed analysis of structural changes during channel activation and deactivation, and the identification of the functional consequences of gene mutations. Using these approaches to monitor various aspects of the complex machinery involved in the generation and regulation of ion channels led to recent developments that were the focus of the Jacques Monod Conference on ligand-gated ion channels held in Roscoff, France, 24–29 May 2019. The reviews published in this symposium issue of The Journal of Physiology highlight recent advances in the field. Most of our current knowledge about ionotropic glutamate receptors (iGluRs) is based on studies from mammals. Detailed pharmacological work allowed the categorization of glutamate receptors that form ligand-gated ion channels into distinct subtypes: AMPA, kainate, delta and NMDA receptors. Subsequent phylogenetic analysis in various species in the tree of life led to the discovery of homologue receptors in plants and invertebrates, including several important model organisms. Mayer (2021) highlights the functional properties of invertebrate iGluRs that might seem surprising at first; for example, Drosophila kainate receptors are not activated by kainate, and AMPA receptors are only very weakly activated by AMPA. While the structure of eukaryotic iGluRs is highly conserved, the specific ligand binding functions we know so well in mammals are not a universal feature in the animal kingdom of life. This review shows when and why iGluRs in invertebrates are different from their mammalian counterparts, while we also gain important insights into the phylogenetic relationship of glutamate receptors. Among iGluRs, members of the NMDA receptor family are equipped with several functional features that cannot be found in other iGluRs, such as their voltage-dependent magnesium block and dual agonist dependence. Stroebel & Paoletti (2021) investigate the diversity of NMDA receptors from an evolutionary perspective. How did their distinctive features emerge? How did evolution shape the structure and function of NMDA receptors? This review aims to answer these questions while shedding light on the intricate relationship between structure and function unique to NMDA receptors. AMPA receptors production is a multi-step process in the endoplasmic reticulum (ER) conducted by helper proteins. Schwenk & Fakler (2021) investigate the questions of how these receptors are built in neurons. What are the steps and key players in AMPA receptor biogenesis? The review explores how the steps involved in the biogenesis of AMPA receptors could offer new mechanisms to control and regulate synaptic signalling. Transmembrane auxiliary proteins influence both receptor biogenesis and localization at the synapse. Cull-Candy & Farrant (2021) address the question of how these proteins regulate the level of calcium-permeable AMPA receptors (CP-AMPRs) at the synapse. This change in the expression level of CP-AMPRs is known to influence synaptic plasticity at various neuronal connections. This review explores which forms of plasticity CP-AMPRs are involved, the hallmark properties of CP-AMPRs, and how various auxiliary proteins modify these features and CP-AMPA receptor-dependent synaptic plasticity. Ion channels are not solely located in the nervous system; they play critical roles in several physiological processes, including the establishment of ionic homeostasis in various parts of the body. Yelshanskaya et al. (2021) explore the function of the principal epithelial calcium channels for Ca2+ absorption in the intestines. This