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Arij Daou BSC 5936 – Fall 2011

Annotated Bibliography - Sodium Channels and Nonselective Cation Channels

Catterall WA, Goldin AL, Waxman SG. “International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.” Pharmacol Rev. 2005; (4):397-409. - A good review on the family of voltage-gated sodium channels (VGSCs), particularly Nav 1.1-1.8. They discuss the general structure of VGSCs, their functional subunits, classifications, genes encoding the channels, and general pharmacological details. I liked about this paper the nomenclature and the way they classified the different isoforms of VGSCs listing details of their molecular information, associated subunits, activation and inactivation details, activators and blockers, gating modifiers and physiological functions.

Zhao Y, Yarov-Yarovoy V, Scheuer T, Catterall WA. “A gating hinge in Na channels; a molecular switch for electrical signaling.” . 2004; 41(6):859-65. - Here they provide functional evidence suggesting gating via the bending of the inner pore helix at a glycine hinge in bacterial sodium channels NaChBac. When they mutated glycine 219 in the S6 segment to proline, which favors bending of the , activation of the was greatly enhanced and its voltage dependence was shifted. Moreover, its inactivation and deactivation were greatly slowed down. This paper showed that glycine 219 at segment S6 serves as a molecular hinge for inactivation of the sodium channels in bacterial cells.

Catterall WA. “Neurotoxins that act on voltage-sensitive sodium channels in excitable membranes.” Annu Rev Pharmacol Toxicol. 1980; 20:15-43. - A variety of VGSC toxins exist in nerve, and skeletal muscle. These include and , , , , grayanotoxin, scorpion venoms and sea anemone nematocysts. This paper is a great review paper where Catterall WA discusses the chemical nature of these toxins, the mechanisms of inhibition of sodium channels by the toxins, the receptor sites that interact with the toxins, and how the toxins alter activation and inactivation of sodium channels. This paper gave an insight into the cellular and molecular mechanisms of action of the toxins.

Waxman SG, Dib-Hajj S, Cummins TR, Black JA. “Sodium Channels and Pain.” Proc Natl Acad Sci U S A. 1999; 96(14):7635-9. - Sodium channels are implicated in pain and hyperexcitability. This is a good paper that sheds light on this topic. The authors used molecular, electrophysiological, and pharmacological techniques to unveil what types of sodium channels underlie hyperexcitability in sensory after injury. They demonstrate that sodium channels are encoded by mRNAs within the dorsal root ganglion (DRG) neurons, and that after injury of the DRG neurons, sodium channels expression in these neurons is dramatically altered, and this change is accompanied by changes in their electrophysiological properties where the neurons tend to fire with high firing frequencies causing hyperexcitability, the main ingredient of pain in these cells.

Rowe AH, Xiao Y, Scales J, Linse KD, Rowe MP, Cummins TR, Zakon HH. “Isolation and Characterization of CvIV4: A Pain Inducing α- Scorpion Toxin.” PLoS One. 2011; 6(8):e23520. - In this paper, the authors focus on a particular kind of sodium channel toxins, the α- Scorpion Toxin that they extract from the Buthidae scorpions in Arizona mountains. If not deadly, this venom induces strong pain in humans. The α- scorpion toxins are known to bind to the S3-S4 loop at domain IV of the voltage-gated sodium channel and alters the gating mechanism by trapping the S4 subunit in its outward position and thereby slowing inactivation. After applying HPLC twice on the venom and isolating the pain-inducing subunit of it (CvIV4), they tested it on the different isoforms of sodium channels and showed that the toxin greatly disrupts the inactivation of isoforms Nav 1.2, Nav 1.3, Nav 1.4 and Nav 1.7 by slowing it down. However, it has no effect on the TTX-resistant isoforms Nav 1.8 and Nav 1.9. And since Nav 1.7 had been showing to be directly implicated in pain, it means that the toxin is only targeting Nav 1.7 to induce pain. Moreover, they showed that even though the toxin is slowing down inactivation, it has no effect on the voltage dependence of inactivation and activation.

Volkers L, Kahlig KM, Verbeek NE, Das JH, van Kempen MJ, Stroink H, Augustijn P, van Nieuwenhuizen O, Lindhout D, George AL Jr, Koeleman BP, Rook MB. “Nav 1.1 dysfunction in genetic epilepsy with febrile seizures-plus or Dravet syndrome.” Eur J Neurosci. 2011; doi: 10.1111/j.1460-9568. - Mutations in the SCN1A gene, the gene encoding for the voltage-gated sodium channel isoform Nav 1.1, had been shown to be associated with epilepsy febrile seizures or Dravet syndrome (DS). Here, they studied four mutations in the SCN1A gene (R859H, R865G, R946C and R946H). They found that R946C and R946H mutations are associated with the Dravet phenotype and are mutations in the pore-loop region of the SCN1A gene. However, R859H or R865G mutations are mutations in voltage sensor domain of the alpha subunit (domain II, S4 segment) and they produced sodium currents similar to those in wild-type channels; however, they were associated with a reduction in voltage-dependent steady-state channel availability and a delayed recovery from fast inactivation.

He B, Soderlund DM. “Human embryonic kidney (HEK293) cells express endogenous voltage-gated sodium currents and Nav 1.7 sodium channels.” Neurosci Lett. 2010; 469(2):268-72 - Here the authors used Human Embryonic Kidney (HEK293) cells for the expression of voltage-gated sodium channels, while focusing on the Nav 1.7 isoform. They applied patch clamp analysis and identified the inward Na+ currents, their peak amplitudes, activation and inactivation curves and other physiological properties. Applications of Cadmium and Tetrodoxin showed that both drugs reduce the peak current amplitude but with a stronger effect of TTX; moreover, joint application of cadmium and TTX was additive. After that, they tested the effect of Tefluthrin, and they revealed that it prolonged the inactivation of transient currents and induced slowly decaying tail currents.

Weiss J, Pyrski M, Jacobi E, Bufe B, Willnecker V, Schick B, Zizzari P, Gossage SJ, Greer CA, Leinders-Zufall T, Woods CG, Wood JN, Zufall F. “Loss-of-function mutations in sodium channel Nav 1.7 cause anosmia.” Nature. 2011; 472(7342):186-90 - This is a great paper where the authors show that the Nav 1.7 isoform is required for odour perception in humans. It had been proved before that the loss of function of the gene SCN9A, the gene encoding for the VGSC Nav 1.7, causes an inability to experience pain in humans. Here they show that Nav 1.7 is not only responsible for pain sensation but is also an essential requirement for odour perception. To prove that, they generated KO mice in which Nav 1.7 was removed from all olfactory sensory neurons (OSN). In the absence of Nav 1.7, these neurons still produce odour-evoked action potentials but they fail to initiate synaptic signalling from their axon terminals.

Catterall WA. “From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels.” Neuron. 2000; 26(1):13-25. - This is the main review paper I based my understanding of the molecular and functional roles of voltage-gated sodium channels. It’s is a great paper by Catterall WA. It goes in details to the primary structure of sodium channels, it’s corresponding subunits, domains, segments, loops, activation and inactivation components and all the other units that constitute this transmembrane protein. Catterall describes in it thoroughly the roles of each of these components in determining the behavior of the . He also introduces briefly at the end sodium channelopathies. It is simply a great review paper!

Baker MD, Wood JN. “Involvement of Na+ channels in pain pathways.” Trends Pharmacol Sci. 2001; 22(1):27-31. - This paper is a good review paper that describes the involvement of sodium channels in pain. Particularly, sodium channel subtypes Nav 1.3, Nav 1.7 and Nav 1.8 are associated with nerve injury and inflammation. This paper sheds light on this topic and explores the role of these channels in pain pathways.

URLs: Besides pubmed and the various journals’ websites, here is a list of some other websites: http://www.ionchannels.org/ - This is a good website that contains information about all sorts of ion channels. It also contains pictures, videos, forums for discussion, and links to recent articles in the field. http://neuromuscular.wustl.edu/mother/chan.html - Contains a nice glossary of ion channels, transmitters, receptors and associated diseases. All sorts of channels are listed, their functions, subunits and roles are described, disorders of these channels are explained and the names of the diseases associated. http://nerve.bsd.uchicago.edu/ - This webpage contains various computer simulations of electrophysiology and ion channel mechanisms. Samples of that are the cable properties of the axon, sodium channel simulation and voltage dependent . http://www.whatislife.com/reader/channels/channels.html - A webpage that introduces basic features and functionalities of ion channels. http://www.cellsalive.com/channels.htm - Contains simulations, pictures and several other information on ion channels and their functionalities. http://www.ebi.ac.uk/compneur-srv/LGICdb/LGICdb.php - This URL contains information of all ligand-gated ion channels. It is a database of information where one can download the data in special format. http://highered.mcgraw- hill.com/sites/0072943696/student_view0/chapter8/animation__voltage- gated_channels_and_the_action_potential__quiz_1_.html - A nice animation showing the behavior of sodium and potassium ions upon the generation of an . It also contains animations for several other channels as well contains quizzes that one can take. http://icwww.epfl.ch/~gerstner/SPNM/node15.html - This link contains a “zoo” of ion channels that discuss their electrophysiological properties from a mathematical point of view, their dynamics and the parameters that generate their behavior. http://amrita.vlab.co.in/?sub=3&brch=212&sim=766&cnt=1 - Being a Biomathematician also, I liked this webpage because it introduces the neurophysiology of the sodium ion channel and describes how to model its behavior mathematically. http://www.life.umd.edu/grad/mlfsc/zctsim/ionchannel.html - Describes the action of TTX on the sodium channel.