| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Viewpoint |
1 Faculty of Life Sciences, The University of Manchester, 2nd Floor, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK
(Received 2 November 2006;
accepted after revision 6 November 2006; first published online 10 November 2006)
Corresponding author I. M. Fearon: Faculty of Life Sciences, The University of Manchester, 2nd Floor, Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK. Email: ian.fearon{at}manchester.ac.uk
Co-ordinated activity of ion channels controls both the electrical activity and the contraction of the heart. Individual cardiac cell types perform specific tasks, and their electrical activity is tailored to their assigned role in cardiac function by the differential expression of diverse types of ion channels. Purkinje fibres are specialized sets of cells that conduct the passage of action potentials to the apex of the heart, ensuring not only a rapid but also a spatially and temporally co-ordinated spread of excitation across both ventricles. In this issue of Experimental Physiology, Vassalle et al. (2007) use biophysical and pharmacological profiling to provide fresh insight into the nature of the sodium channels responsible for shaping the distinct electrical properties of Purkinje fibre cells. Importantly, they reveal that the sodium current responsible for the prolonged plateau of the Purkinje action potential is distinct from that involved in the action potential upstroke and is produced by the flow of sodium ions through a discrete voltage-gated sodium (NaV) channel.
NaV channels are found in most excitable cells and are responsible for the initiation and propagation of electrical signals. In cardiac muscle cells, NaV channel opening causes a fast-activating inward sodium current (INa1), which mediates the rapid membrane-depolarizing upstroke of the action potential. This leads to the opening of voltage-gated calcium channels, allowing the entry of calcium into the cell and triggering contraction. Nine genes encoding distinct NaV
-subunit isoforms (NaV1.1 to NaV1.9) have been identified in the human genome. Of these, NaV1.5 is responsible for the action potential upstroke in atrial and ventricular muscle, and also in the conductive cells of the Purkinje fibres. In contrast to contractile cells, however, the Purkinje cells exhibit a greatly prolonged action potential. This arises owing to a prolonged sodium current (termed INa2), which is sensitive to tetrodotoxin (TTX; a toxin isolated from the puffer fish). Indeed, TTX has long been known to shorten the action potential plateau in Purkinje cells (Coraboeuf et al. 1979), while it is relatively ineffective against the action potential upstroke in both these and contractile cells. Several theories have evolved to explain the mechanistic basis of the Purkinje INa2 current, some of which propose that it arises from persistent openings or other biophysical properties of INa1. In this issue of Experimental Physiology, however, Vassalle and colleagues provide strong evidence that INa2 is mediated by a slowly inactivating sodium channel, which is TTX sensitive and distinct from the NaV1.5 channel responsible for INa1.
How might a Purkinje cell generate a distinct, slowly inactivating sodium current? What might be its molecular basis? The ‘skeletal’ NaV1.4 channel possesses the required characteristics of INa2, since it is TTX sensitive and activates in the correct voltage range (Catterall et al. 2005). Preliminary data from Vassalle's laboratory show the presence of NaV1.4 protein in canine Purkinje fibres (see Discussion by Vassalle et al. 2007). Moreover, when expressed in Xenopus laevis oocytes, NaV1.4 channels display the persistent opening requisite for a role in the prolonged Purkinje action potential plateau (Chahine et al. 1994). When NaV1.4 was expressed in mammalian (HEK293-derived) cells, however, persistent currents were not observed (e.g. Chahine et al. 1994). This does not rule out a role for NaV1.4 in the prolonged action potential, but does suggest that auxiliary subunits and/or interacting proteins could modify the properties of the channel in different cell types. Purkinje fibres also express mRNA for the ‘brain type II’ NaV1.2 channel in abundance and at a far greater level than that found in the ventricular myocardium (Haufe et al. 2005). Like NaV1.4, NaV1.2 has high TTX sensitivity (Catterall et al. 2005), activates in the correct voltage range and, at least in the presence of certain auxiliary ß-subunits, exhibits persistent sodium currents (Qu et al. 2001). A further possibility is that a specific channel phenotype arises from genetic variations of a previously identified channel type, and certainly alternative splicing of sodium channel genes has the potential to create functional variation and diversity in sodium channel function (e.g. Zimmer et al. 2002).
Clearly, the excellent work of Vassalle and colleagues provides novel insight into the ionic mechanisms underlying the prolonged action potential of the Purkinje cells. Clearly, recombinant systems offer the potential to match expressed channels with electrophysiological phenotypes, although the sheer number of NaV channels and potential combinations of coexpressed auxiliary subunits may limit their usefulness. Perhaps by embracing modern molecular technologies, such as targeted gene knockouts, Vassalle and colleagues have the potential to pinpoint the molecular nature of the INa2 channel, and to further define a role of this channel in the cause and treatment of arrhythmic syndromes.
References
Catterall WA, Goldin AL & Waxman SG (2005). International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57, 397–409.
Chahine M, Bennett PB, George AL Jr & Horn R (1994). Functional expression and properties of the human skeletal muscle sodium channel. Pflugers Arch 427, 136–142.[CrossRef][Medline]
Coraboeuf E, Deroubaix E & Coulombe A (1979). Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Physiol Heart Circ Physiol 236, H561–H567.
Haufe V, Cordeiro JM, Zimmer T, Wu YS, Schiccitano S, Benndorf K & Dumaine R (2005). Contribution of neuronal sodium channels to the cardiac fast sodium current INa is greater in dog heart Purkinje fibers than in ventricles. Cardiovasc Res 65, 117–127.
Qu Y, Curtis R, Lawson D, Gilbride K, Ge P, DiStefano PS, Silos-Santiago I, Catterall WA & Scheuer T (2001). Differential modulation of sodium channel gating and persistent sodium currents by the ß1, ß2, and ß3 subunits. Mol Cell Neurosci 18, 570–580.[CrossRef][Medline]
Vassalle M, Bocchi L & Du F (2007). A slowly inactivating sodium current (INa2) in the plateau range in canine cardiac Purkinje single cells. Exp Physiol 92, 161–173.
Zimmer T, Bollensdorff C, Haufe V, Birch-Hirschfeld E & Benndorf K (2002). Mouse heart Na+ channels: primary structure and function of two isoforms and alternatively spliced variants. Am J Physiol Heart Circ Physiol 282, H1007–H1017.
Acknowledgements
Research in the laboratory of I.M.F. is funded by the British Heart Foundation and Heart Research UK.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
