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J Physiol Volume 566, Number 2, 641-, July 15, 2005 DOI: 10.1113/jphysiol.2005.566101
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LETTERS

‘Dynamic clamp’ in cardiac electrophysiology

In the recent study ‘Role of the transient outward current (Ito) in shaping canine ventricular action potential – a dynamic clamp study’ by Sun & Wang (2005), the authors used the ‘dynamic clamp’ technique to inject a computer-calculated current into an isolated ventricular myocyte under current-clamp conditions, thus simulating an ion channel conductance in real time. This technique enabled them to nicely demonstrate how Ito modulates the ventricular action potential. The ‘dynamic clamp’ technique was introduced in neurobiology by Sharp et al. (1992, 1993a,b) to create an artificial electrical synapse between two isolated neurones or insert an artificial membrane conductance in a single isolated neurone. Similar techniques were independently developed by Robinson & Kawai (1993) and Hutcheon et al. (1996), presented as ‘conductance injection’ and ‘reactive current clamp’, respectively. The ‘dynamic clamp’ has become a widely used tool for the study of neural systems at the cellular and circuit levels, inserting artificial conductances in individual neurones (Sharp et al. 1993a; Hutcheon et al. 1996), coupling biological neurones (Sharp et al. 1992; Elson et al. 1998), and coupling model and biological neurones (Le Masson et al. 1995; Manor & Nadim, 2001).

In their paper, Sun & Wang (2005) state that ‘the dynamic clamp was first developed as a neurobiological tool over a decade ago’ and that ‘the dynamic clamp is a new and effective tool to study the ionic basis of the electrical properties of cardiac cells’. I would like to place these statements in the proper historical context. The dynamic clamp is certainly an effective but not a new tool in cardiac electrophysiology. Actually, the technique was first developed over 25 years ago by Scott (1979) who used it as a tool to study the mutual synchronization of two small clusters of spontaneously beating embryonic chick ventricular cells. He created an ‘Ersatz Nexus’ by injecting an ionic current into each cluster corresponding to the current that would have flown if the clusters would have been physically coupled by gap junctions. One decade later, a related technique was independently developed by Joyner and coworkers to study the electrical interactions of isolated cardiomyocytes through an artificial gap junction (Tan & Joyner, 1990; Joyner et al. 1991). Initially, this ‘coupling clamp’ technique, which has been adopted by other groups (e.g. Watanabe et al. 1995; Huelsing et al. 2001), was implemented by an analog circuit, but in subsequent studies a computer-based system was used, which allowed one of the myocytes to be replaced with a real-time simulation of such cell (Wilders et al. 1996a,b). The system has also been modified to insert a simulated conductance in an isolated cardiomyocyte (e.g. Wagner et al. 2004), as in the study by Sun & Wang (2005). Recently, Berecki et al. (2005) extended this technique by effectively replacing a native ionic current of a ventricular myocyte with wild-type or mutant current recorded from a HEK-293 cell that is voltage-clamped by the free-running action potential of the ventricular myocyte (‘dynamic action potential clamp’). In summary, the dynamic clamp started its life in cardiac electrophysiology as early as 1979 and has proven to be an effective tool since then.

Ronald Wilders

Department of Physiology Academic Medical Center University of Amsterdam Amsterdam, the Netherlands Meibergdreef 15, 1105 AZ Amsterdam the Netherlands Email: r.wilders{at}amc.uva.nl

References

Berecki G, Zegers JG, Verkerk AO, Bhuiyan ZA, de Jonge B, Veldkamp MW, Wilders R & van Ginneken ACG (2005). HERG channel (dys) function revealed by dynamic action potential clamp technique. Biophys J 88, 566–578.[Abstract/Free Full Text]

Elson RC, Selverston AI, Huerta R, Rulkov NF, Rabinovich MI & Abarbanel HDI (1998). Synchronous behavior of two coupled biological neurons. Phys Rev Lett 81, 5692–5695.[CrossRef]

Huelsing DJ, Pollard AE & Spitzer KW (2001). Transient outward current modulates discontinuous conduction in rabbit ventricular cell pairs. Cardiovasc Res 49, 779–789.[Abstract/Free Full Text]

Hutcheon B, Miura RM & Puil E (1996). Models of subthreshold membrane resonance in neocortical neurons. J Neurophysiol 76, 698–714.[Abstract/Free Full Text]

Joyner RW, Sugiura H & Tan RC (1991). Unidirectional block between isolated rabbit ventricular cells coupled by a variable resistance. Biophys J 60, 1038–1045.[Abstract/Free Full Text]

Le Masson G, Le Masson S & Moulins M (1995). From conductances to neural network properties: analysis of simple circuits using the hybrid network method. Prog Biophys Mol Biol 64, 201–220.[CrossRef][Medline]

Manor Y & Nadim F (2001). Frequency regulation demonstrated by coupling a model and a biological neuron. Neurocomputing 38–40, 269–278.[CrossRef]

Robinson HP & Kawai N (1993). Injection of digitally synthesized synaptic conductance transients to measure the integrative properties of neurons. J Neurosci Meth 49, 157–165.[CrossRef][Medline]

Scott S (1979). Stimulation Simulations of Young Yet Cultured Beating Hearts. PhD Thesis, State University of New York at Buffalo.

Sharp AA, Abbott LF & Marder E (1992). Artificial electrical synapses in oscillatory networks. J Neurophysiol 67, 1691–1694.[Abstract/Free Full Text]

Sharp AA, O'Neil MB, Abbott LF & Marder E (1993a). Dynamic clamp: computer-generated conductances in real neurons. J Neurophysiol 69, 992–995.[Abstract/Free Full Text]

Sharp AA, O'Neil MB, Abbott LF & Marder E (1993b). The dynamic clamp: artificial conductances in biological neurons. Trends Neurosci 16, 389–394.[CrossRef][Medline]

Sun X & Wang H-S (2005). Role of the transient outward current (Ito) in shaping canine ventricular action potential – a dynamic clamp study. J Physiol 564, 411–419.[Abstract/Free Full Text]

Tan RC & Joyner RW (1990). Electrotonic influences on action potentials from isolated ventricular cells. Circ Res 67, 1071–1081.[Abstract/Free Full Text]

Wagner MB, Kumar R, Joyner RW & Wang Y (2004). Induced automaticity in isolated rat atrial cells by incorporation of a stretch-activated conductance. Pflugers Arch 447, 819–829.[CrossRef][Medline]

Watanabe EI, Honjo H, Anno T, Boyett MR, Kodama I & Toyama J (1995). Modulation of pacemaker activity of sinoatrial node cells by electrical load imposed by an atrial cell model. Am J Physiol 269, H1735–H1742.[Medline]

Wilders R, Kumar R, Joyner RW, Jongsma HJ, Verheijck EE, Golod D, van Ginneken ACG & Goolsby WN (1996a). Action potential conduction between a ventricular cell model and an isolated ventricular cell. Biophys J 70, 281–295.[Abstract/Free Full Text]

Wilders R, Verheijck EE, Kumar R, Goolsby WN, van Ginneken ACG, Joyner RW & Jongsma HJ (1996b). Model clamp and its application to synchronization of rabbit sinoatrial node cells. Am J Physiol 271, H2168–H2182.[Medline]




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