J Physiol 596.10 (2018) pp 1829–1832 1829
EDITORIAL
Shared and unique aspects of issue of The Journal of Physiology brings with few side effects is afforded by its pre- ligand- and voltage-gated together three timely review articles and ferred high-affinity binding to nematode ion-channel gating an original paper that capture some of the glutamate-gated chloride channels. ideas, discussions and debates that arose Dr Cecilia Bouzat from the National Derek Bowie during the symposium. University of the South (UNS), Bah`ıa Department of Pharmacology and Thera- Dr Yoshihiro Kubo from Japan’s National Blanca, Argentina, presented recent work peutics, McGill University, Montr´eal, Institute for Physiological Sciences opened from her lab on the functional and Qu´ebec H3G 1Y6, Canada the symposium by presenting recent data pharmacological properties of α7 subunit- Email: [email protected] from his lab where they looked at the containing nicotinic acetylcholine receptors Edited by: Ole Petersen unexpected effect of the broad-spectrum (nAChRs) (daCosta et al. 2011; Andersen antiparasitic agent ivermectin on the G- et al. 2013, 2016; Nielsen et al. 2018). protein-gated inwardly rectifying K+ (or Although nAChRs are expressed through- α Ligand- and voltage-gated ion channels GIRK) channel (Chen et al. 2017). Since out the body, 7 receptors are especially form a large superfamily of membrane- its discovery in soil samples of bacteria concentrated in the mammalian brain bound signalling proteins that fulfil many taken near a Japanese golf course in the where they exhibit both ionotropic and important roles in health and disease 1970s (Laing et al. 2017), ivermectin has metabotropic functions (Wu et al. 2016; (Hille, 2001). Voltage-gated ion channels proven to be one of the most effective Kabbani & Nichols, 2018). They are are primarily responsible for the generation drugs used by veterinarians and health also implicated in several CNS disorders and propagation of action potentials in professionals to combat parasite infection. (Dineley et al. 2015) and consequently excitable tissue (Stuart et al. 1997; Catterall Although its anthelmintic action is there has been a need to develop selective et al. 2005; Jan & Jan, 2012) whereas primarily mediated by targeting the activity drugs. The review article by Bouzat and ligand-gated ion channels constitute the of nematode glutamate-gated chloride colleagues (Bouzat et al. 2018) highlights hardwiring of chemical synapses – though channels to curtail motility, feeding these recent advances in our understanding α α they also fine tune synaptic strength during and reproductive behaviour (Yates et al. of the 7 nAChR. Potentiation of the 7 periods of sustained patterned activity 2003), ivermectin has also been shown to receptor has been identified as a novel and altered homeostasis (Turrigiano, 2008; affect other ion channel families such as therapeutic strategy to treat several neuro- Nicoll, 2017). Together, the combined GABAA, glycine and nicotinic acetylcho- degenerative disorders, including Alzh- activity of ligand- and voltage-gated ion line receptors (Wolstenholme & Rogers, eimer’s and Parkinson’s diseases, and channels gives rise to many complex physio- 2005). This multifaceted nature of inflammatory disorders, whereas drugs logical processes from cardiac and skeletal ivermectin pharmacology is the main topic which reduce receptor activity may be bene- muscle contraction to the more enigmatic of the comprehensive review by Chen and ficial in the treatment of cancer cell behaviours of the CNS such as cognition Kubo where they explore shared and unique proliferation (Bouzat et al. 2018). and memory. modulatory properties of ivermectin on a Dr Frank Bosmans from Johns Hopkins The study of ion channels has undergone variety of ligand-gated ion channels (Chen University in Baltimore, MD, USA talked unprecedented advances in recent years & Kubo, 2018). Insight into ivermectin’s about the pioneering work that he and with the convergence of several scientific action on each ion channel target is his colleagues have performed using disciplines on this important research topic. beautifully illustrated by the authors’ animal toxins to probe the functional Structural biology has emerged as a effective use of X-ray crystallographic data behaviour of voltage-gated ion channels, + The Journal of Physiology leading approach to understand ion channel to compare and contrast the structural particularly voltage-gated Na channels function as well as drug action (Gouaux determinants of each binding pocket. (Nav) (Bosmans & Swartz, 2010; Kalia & Mackinnon, 2005). Furthermore, recent Given its hydrophobicity, ivermectin binds et al. 2015). Voltage-gated Nav channels advances in genetic manipulations, parti- to residues lining the transmembrane are primarily responsible for the rapid cularly in rodents, have permitted ion (TM) regions of Cys-loop ligand-gated ion upstroke of the action potential in cardiac channel families to be assigned distinct channels, such as the nematode glutamate- and skeletal muscle as well as being integral roles in health and disease. To explore this gated chloride channels and mammalian to the complex firing properties of central emerging area of physiology, The Journal of glycine receptors. The binding of ivermectin neurons. Not surprisingly, therefore, Nav Physiology sponsored a symposium at the near the extracellular surface of the plasma channels are involved in many physiological 2017 International Union of Physiological membrane is critical as it induces the processes and have also been implicated Sciences meeting in Rio de Janeiro, Brazil rotation of TM regions to facilitate channel in numerous pathologies including cardiac entitled ‘Shared and unique aspects of the opening. Surprisingly, however, ivermectin dysfunction, neuropathic pain and genetic gating mechanisms of ligand- and voltage- binds to GIRK channels on a different forms of epilepsy, such as Dravet syndrome gated ion-channels’. Chaired by Journal site, which lies at the interface of the TM (Abriel, 2010; Catterall, 2012; Waxman, editors Drs Yoshihiro Kubo and Derek region and intracellular domains (Chen 2013; Chen-Izu et al. 2015). Given all Bowie, it brought together five researchers et al. 2017). The authors conclude that of this, the Nav channel community has (see Fig. 1) whose work is at the forefront of although ivermectin binds to many ion been developing a comprehensive under- this rapidly developing field of study. This channel targets, its clinical value as a drug standing of how the structural architecture