Abstract
Ion channels contribute fundamental properties to cell membranes. Although highly diverse in conductivity, structure, location, and function, many of them can be regulated by common mechanisms, such as voltage or (de-)phosphorylation. Primarily considering ion channels involved in the nociceptive system, this review covers more novel and less known features. Accordingly, we outline noncanonical operation of voltage-gated sodium, potassium, transient receptor potential (TRP), and hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Noncanonical features discussed include properties as a memory for prior voltage and chemical exposure, alternative ion conduction pathways, cluster formation, and silent subunits. Complementary to this main focus, the intention is also to transfer knowledge between fields, which become inevitably more separate due to their size.
Highlights
The main aim of this review is to illustrate unexpected behaviour of ion channels, which might cross-pollinate advances between fields
Slow inactivation is different depending on Nav channel isoform, and the exact molecular determinants for slow inactivation are difficult to pinpoint as many positions and residues have been described that seem to affect slow inactivation
Slow inactivation has been found to be modulated by different mutations in Nav1.7 that cause the chronic pain syndrome erythromelalgia [17,18,19,20,21,22,23,24,25,26,27,28,29]
Summary
The main aim of this review is to illustrate unexpected behaviour of ion channels, which might cross-pollinate advances between fields. To at least partly fulfil this aim, we restricted coverage to the pain field and the subsections are written by authors with a focus on the respective ion channel families. We consider as canonical any feature of an ion channel pore-forming protein, which can allow the flow of ions across membranes [1]. Common features include regulation of the permeation (gating) by ligands and voltage; preference or selectivity for some ions over others; interaction with other cytoplasmic or membrane proteins; trafficking between the plasma membrane and reserve pools; heteromerisation of the channels; modulation by intracellular cascades e.g., by a change of phosphorylation state; and a change of expression levels, e.g., in inflammatory conditions. Less common and more on the line between canonical and noncanonical are features such as interaction with phospholipids or accessory subunits
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