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Topical Reviews |
1 Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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(Received 22 June 2006;
accepted after revision 21 July 2006;
first published online 27 July 2006)
Corresponding author R. Wilders: Department of Physiology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. Email: r.wilders{at}amc.uva.nl
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Introduction |
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TopAbstractIntroductionReferences |
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Recent studies in cardiac electrophysiology (Berecki et al. 2005, 2006; Sun & Wang, 2005; Dong et al. 2006; Wang et al. 2006) demonstrate the growing interest in the application of ‘dynamic clamp’, which is a less well known but very powerful electrophysiological technique. In general, this technique is used to inject a current into a myocyte in current clamp mode. However, unlike classic current clamp, this current is not known a priori. Usually, the current is a function of the free-running membrane potential of the myocyte. Typically, this current mimics the existence of an additional ionic conductance in the cell membrane. The dynamic clamp technique thus operates in a cyclic way: in a continuous loop, the membrane potential is recorded into a computer that calculates the current to be injected and lets the patch clamp amplifier inject this current.
In cardiac electrophysiology, the dynamic clamp technique has been used in three different experimental configurations. In this review, each of these configurations is described. Also, directions are given for the implementation of dynamic clamp, which is fundamentally more difficult than traditional voltage clamp or current clamp, because it requires the real-time evaluation and injection of simulated membrane current.
History of dynamic clamp
As briefly discussed before (Wilders, 2005), the dynamic clamp was introduced by Scott (1979) in a study of the bidirectional interaction of two spontaneously beating clusters of embryonic chick ventricular cells, as an extension of his work on phase resetting properties of individual clusters. He designed a system in which two isolated cell clusters not in physical contact with each other could be electrically coupled at any desired value of intercellular resistance by means of an external circuit that continuously applied time-varying currents to each cluster with a sign and magnitude that would have been present if the cells had been physically coupled by gap junctions (or ‘nexus’). He impaled each cell cluster with a microelectrode and thus recorded its membrane potential. He then simulated intercellular electrical coupling through gap junctions by creating a physical connection between the two clusters through an analog circuit, named ‘Ersatz Nexus’. As illustrated in Fig. 1, the circuit was designed to inject a current into each of the clusters such that they are effectively coupled by a nexus resistance RN. If Vm,1 and Vm,2 are the time-varying membrane potentials of the two clusters, then the time-varying current IN injected into cluster 2 is given by IN = (Vm,1 – Vm,2)/RN (Ohm's law), whereas the inverted current is injected into cluster 1. Thus, a ‘nexus current’ IN flows between cluster 1 and cluster 2.
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About one decade later, Joyner and coworkers independently developed an analog ‘coupling clamp’ circuit – essentially similar to Scott's Ersatz Nexus – that could be used to simulate gap junctional coupling between two isolated myocytes (Tan & Joyner, 1990; Tan et al. 1991; Joyner et al. 1991). Shortly after the introduction of the coupling clamp technique in cardiac electrophysiology, similar techniques were independently introduced in neurophysiology by Sharp et al. (1992, 1993a,b) and Robinson & Kawai (1993), named ‘dynamic clamp’ and ‘conductance injection’, respectively, with some debate on who was first (Robinson, 1994; Sharp et al. 1994), and by Hutcheon et al. (1996), named ‘reactive current clamp’. Although the dynamic clamp has its origin in cardiac electrophysiology, it is now more common in neurophysiology, where it has particular applications, including the simulation of synaptic activity. These applications have been described in recent reviews with emphasis on neurophysiology (Prinz et al. 2004; Goaillard & Marder, 2006).
Dynamic clamp configurations
Based on the experimental setting, three dynamic clamp configurations can be distinguished in cardiac electrophysiology. Each of these configurations is discussed and illustrated below.
Coupling clamp.
Originally, dynamic clamp was used to create electrical connections between myocytes, thus simulating intercellular electrical coupling through gap junctions (‘coupling clamp’). Figure 2A illustrates how coupling clamp is accomplished. Electrical recordings are made from two isolated myocytes, both in current clamp mode, thus requiring two patch clamp amplifiers. These myocytes can either be in one cell chamber on a single electrophysiological setup or in separate recording chambers on two different electrophysiological setups. The membrane potentials Vm,1 and Vm,2 of the two myocytes are sampled into a personal computer. This computer then computes the coupling current Ic flowing from myocyte 1 to myocyte 2, based on Vm,1 and Vm,2, and sends command potentials to the amplifiers such that the appropriate current is injected into each of the myocytes, where it contributes to net membrane current and thus affects the membrane potential. Since both Vm,1 and Vm,2 may change rapidly with time, this process requires a high update rate, i.e. a small cycle time 
t, typically 100 µs or less.
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As illustrated in Fig. 3, the dynamic clamp configuration of Fig. 2A could be used to study the synchronization process of SA nodal pacemaker cells in detail. Similar experiments were carried out by Spitzer et al. (1997), who used an analog coupling clamp circuit to study the mutual entrainment of two adult pacemaker cells isolated from the rabbit atrioventricular (AV) node upon coupling through a 500 M
resistance (equivalent to a coupling conductance of 2 nS). To minimize intracellular dialysis, the nystatin-perforated patch clamp technique was used to record the membrane potentials and currents of these nodal cells. In each of the four AV nodal cell pairs studied, the two cells showed frequency entrainment, but not waveform entrainment, upon coupling. Coupling decreased the firing rate of the intrinsically faster beating cell and increased that of the intrinsically slower beating cell to a common intermediate rate. The common firing rate (192 ± 55 beats min–1, mean ±
S.D.) was closer to the firing rate of the intrinsically faster beating cell (197 ± 54 beats min–1) than that of the intrinsically slower beating cell (177 ± 54 beats min–1). These values are remarkably similar to those obtained in five SA nodal cell pairs by Verheijck et al. (1998). In these cell pairs, the common firing rate was 191 ± 33 beats min–1, whereas the firing rate of the intrinsically faster beating cell was 204 ± 32 beats min–1 and that of the intrinsically slower beating cell was 166 ± 39 beats min–1.
Other investigators have used an analog coupling clamp circuit in studies of the modulation of action potential conduction between two isolated guinea pig ventricular myocytes by calcium current (Sugiura & Joyner, 1992), electrotonic modulation of SA node pacemaker activity by atrial muscle (Watanabe et al. 1995), interactions between Purkinje and ventricular myocytes (Huelsing et al. 1998, 1999, 2000, 2003), beat-to-beat repolarization variability in ventricular myocytes (Zaniboni et al. 2000), and effects of transient outward current inhibition on conduction between ventricular myocytes (Huelsing et al. 2001). In several of these studies, one of the myocytes of Fig. 2A was replaced with an RC circuit as a model of an atrial or ventricular myocyte.
Model clamp. Dynamic clamp may also be used to simulate the presence of an additional conductance in the membrane of a single isolated myocyte. In this configuration (Fig. 2B), the membrane potential Vm of the myocyte is continuously sampled into a personal computer, which calculates the Vm-dependent current Ix and sends a command potential to the amplifier to inject this current into the myocyte. This configuration has been referred to as ‘model clamp’ (Wilders et al. 1996b), because a model-based current is injected into the myocyte. In neurophysiology, it has been named ‘model reference current injection’ (Butera et al. 2001; Raikov et al. 2004).
A relatively simple application of the model clamp technique is shown in Fig. 4. Verkerk et al. (2000) used this technique to inject an ohmic current with a reversal potential of –40 mV and an adjustable conductance Gx into an isolated human ventricular myocyte. This current represented the ‘injury current’ flowing from normal myocardium to ischaemic tissue, which is known to contain inexcitable cells that are depolarized to about –40 mV (Downar et al. 1977). In the absence of injury current, i.e. with Gx
= 0 (Fig. 4, green lines), the ventricular myocyte has a resting potential of –82 mV and an APD of 
420 ms. Upon the introduction of injury current with a conductance of 10 nS, the APD shortens to 180 ms and the resting potential depolarizes by 3–4 mV (Fig. 4, blue lines). Increasing the injury conductance to 20 nS induces further APD shortening and depolarization of the resting potential (Fig. 4, red lines). However, the injury current did not induce afterdepolarizations, in contrast with postulations made in previous studies (see Janse & Wit, 1989). These only occurred if its reversal potential was set to less negative potentials (Verkerk et al. 2000). Similar findings had previously been made in guinea pig ventricular myocytes by Kumar & Joyner (1994).
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Model clamp has also proven useful in studies of the differences in bursting properties between isolated mouse pancreatic ß-cells and intact islets, with the more stochastic electrical activity of isolated ß-cells producing faster and less regular intracellular calcium oscillations (Zhang et al. 2003). Introduction of a very small slowly activating inward current into isolated ß-cells converted the electrical activity of spiking or fast-bursting ß-cells to a more islet-like electrical pattern, resulting in more regular and islet-like intracellular calcium oscillations. Similarly, model clamp may prove useful in studies of isolated cardiac pacemaker cells, where the stochastic nature of ion channels influences diastolic depolarization and associated calcium oscillations.
Dynamic action potential clamp. A novel and promising application of the dynamic clamp technique is ‘dynamic action potential clamp’ (Berecki et al. 2005, 2006). In this configuration (Fig. 2C), which was designed to provide a more physiological setting than traditional action potential clamp with a prerecorded action potential, a native ionic current of a cardiomyocyte is pharmacologically blocked and replaced with wild-type or mutant current recorded from a HEK-293 cell that is voltage-clamped by the free-running action potential of the myocyte. In their initial study, Berecki et al. (2005) used this technique to investigate the effects of a long-QT syndrome-related mutation in the human ether-à-go-go-related gene (HERG), which encodes the rapid component of the cardiac delayed rectifier potassium current (IKr). In this case, the myocyte of Fig. 2C was an isolated rabbit ventricular myocyte with its native IKr blocked by E-4031, whereas the HEK-293 cell was transiently transfected with wild-type or R56Q mutant HERG cDNA and thus expressed wild-type or mutant HERG current. In this experimental setting, the wild-type or mutant HERG channels are allowed to follow the natural time course of an action potential (through Vm), upon being simultaneously allowed to contribute current for the generation of this action potential as if they were incorporated into the myocyte (through injection of the HERG current into the myocyte). This is illustrated in Fig. 5, which shows action potentials from the same myocyte generated with the contribution of either wild-type or mutant HERG current (blue and red traces, respectively), obtained by subsequently coupling the myocyte to a HEK-293 cell expressing wild-type current and a HEK-293 cell expressing mutant current. Wild-type and mutant HERG current were both scaled down to produce a HERG current density comparable to the native IKr density of the myocyte, as estimated from the E-4031-sensitive current. This scaling procedure seemed appropriate because the R56Q mutation is associated with altered gating properties rather than impaired trafficking from the endoplasmic reticulum to the cell membrane.
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In their subsequent study, Berecki et al. (2006) used the dynamic action potential clamp technique to investigate the effects of the Y1795C and A1330P long-QT syndrome-related mutations in the SCN5A gene, which encodes the pore-forming subunit of the cardiac sodium channel. In this case, the isolated myocyte of Fig. 2C was replaced with a real-time simulation of a human ventricular myocyte. They demonstrated that the sodium channel mutations resulted in significant action potential prolongation and in a significantly steeper APD–frequency relationship. Also, they showed that the action potential prolongation was more pronounced for the mid-myocardial cell type, resulting in increased APD dispersion. Furthermore, a 2 s pause following rapid pacing resulted in distorted action potential morphology associated with beat-to-beat fluctuations of sodium current. Thus, these dynamic action potential clamp experiments directly demonstrated the arrhythmogenic nature of long-QT syndrome-related mutations in the SCN5A gene.
Setting up dynamic clamp
The value of the dynamic clamp technique in cardiac electrophysiology is becoming widely appreciated. However, implementation of the technique is not straightforward. Therefore, some guidelines for setting up dynamic clamp are given below.
Hardware implementations. If the purpose of dynamic clamp is to compute and inject ohmic current, one may prefer to use custom analog circuitry, similar to that of Scott (1979) and Tan & Joyner (1990). For applications beyond computing and injecting ohmic current there are two commercially available dynamic clamp systems. These are the ITC-18 data acquisition interface (Instrutech Corporation, Port Washington, NY, USA) and the Synaptic Module 1 (SM-1) conductance injection amplifier (Cambridge Conductance, Cambridge, UK). Both are hardware implementations with built-in analog devices, primarily designed to create artificial synapses by injecting a current into a current-clamped neurone based on specific equations that include the membrane potential of the neurone and the conductance and reversal potential of the current (Robinson, 1999). A particular advantage of these hardware implementations is the high speed at which they operate, with a minimal input to output delay of 20 µs.
Software implementations. As an alternative to using dedicated hardware, one may use hardware that is available in most cardiac electrophysiology laboratories, i.e. a PC equipped with a multifunction data acquisition board, and use dedicated software to turn this hardware into a dynamic clamp system. Once running, such a computer-controlled system combines ease of use and high flexibility and is therefore the system of first choice for most applications. Dynamic clamp software is not commercially available, but several research groups have made their custom software publicly available (Table 1). With the exception of ‘DynaClamp’ (Berecki et al. 2005, 2006), all software was mainly developed for use in neurophysiology.
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With regard to the operating system, the available software either runs on Windows or real-time Linux (RT-Linux; Barabanov & Yodaiken, 1997) -based systems. Windows-based software seems attractive for its ease of use, but has particular disadvantages. As listed in Table 1, all software running on Windows systems requires specific hardware components. More importantly, as set out in detail by Butera et al. (2001) and Dorval et al. (2001), Windows is not well suited for running time-critical applications like dynamic clamp. There is no guarantee that voltage and current are continuously updated with the desired small cycle time t (cf. Fig. 2) and with minimal jitter (step-to-step variation in actual t). In the ‘G-clamp’ software by Kullman et al. (2004) this has been overcome by using the Windows computer as a host for an embedded microprocessor that runs a real-time operating system and a multifunction data acquisition board. Thus, it has the disadvantage of requiring additional hardware. Also, it requires the full National Instruments LabVIEW programming environment as well as the LabVIEW-RT real-time module (National Instruments, Austin, TX, USA).
All RT-Linux-based dynamic clamp software requires a PC running the Linux operating system with one of the publicly available hard real-time extensions, e.g. RTAI (Real Time Application Interface; Department of Aerospace Engineering, Polytechnic Institute of Milan, Milan, Italy) or RTLinuxFree (FSMLabs, Socorro, NM, USA). Essentially, as set out in detail by Christini et al. (1999), RT-Linux is a minimal operating system that runs two processes, i.e. a real-time process (top priority, guaranteed timing) and the standard Linux operating system (low priority, absolutely interruptible by the real-time process). The dynamic clamp software has a real-time part that ensures that all time-critical operations are executed in real time, and a non-real-time part that provides for user-control of the program, such as changing parameters and logging of data. To communicate with the data acquisition board, the software uses an open-source project known as Comedi (Control and Measurement Device Interface) that provides the software to control a wide variety of common data acquisition boards, including most of the boards used by cardiac electrophysiologists.
If setting up a computer-controlled dynamic clamp system, an RT-Linux-based system is recommended. First, the RT-Linux operating system and the Comedi library together provide a robust and inexpensive platform that is well-suited for running dynamic clamp software and will probably be available for many years to come. Second, ready-to-use software is available for this platform as well as source code that may function as a template for writing custom dynamic clamp software. Third, developers of the RTLDC and MRCI dynamic clamp software (Table 1) are involved in the ‘Real-Time eXperiment Interface’ (RTXI) project, which is a collaborative open-source software development project aimed at producing an RT-Linux-based software system for hard real-time data acquisition and control applications in biological research.
Limitations
Like any experimental technique, dynamic clamp comes with limitations. An important limitation is that the dynamic clamp mimics the electrical effects of a specific ionic current, but not necessarily its signal conduction effects, because the injected current enters the cell through the patch pipette rather than through real ion channels. Thus, there may be differences in ions carrying the current and in local changes in ion concentration. This limitation can, however, be beneficial if one aims to study electrical effects in isolation. Second, the dynamic clamp can induce errors through latency, i.e. the time lag between acquiring voltage and applying the current based on that voltage. A third limitation is that dynamic clamp, in particular in its model clamp configuration (Fig. 2B), relies on a mathematical description of ion current. A related particular limitation of the dynamic action potential clamp configuration (Fig. 2C) is that ion channels may behave differently, e.g. show different gating properties, in an expression system. Another particular limitation of the dynamic action potential clamp configuration is that the expressed current has to be scaled before injection into the myocyte, with improper determination of the scaling factor as a potential source of errors. The required scaling can, however, also be beneficial in separating the effects of altered gating properties and impaired trafficking. This may prove especially useful when studying ion channel mutations with opposing effects of alterations in gating properties and alterations in channel expression (e.g. Paulussen et al. 2005). Finally, a practical limitation is that dynamic clamp may require simultaneous stable recordings from two myocytes or from one myocyte and one transfected cell (Fig. 2A and C, respectively).
Concluding remarks
Dynamic clamp has been used to provide direct answers to numerous research questions regarding basic cellular mechanisms of cardiac action potential formation, action potential transfer and action potential synchronization in health and disease. Starting with the synchronization experiments by Scott (1979), the dynamic clamp has evolved to a set of elegant techniques that allow detailed studies of the role of specific ionic currents. With the growing interest in the application of dynamic clamp in cardiac electrophysiology, it is anticipated that dynamic clamp will prove a powerful tool in basic research on biological pacemakers and in identification of specific ion channels as targets for drug development.
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