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SYMPOSIUM REPORT |
CNRS UMR 6542, Faculté des Sciences, Université de Tours, Franc
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Abstract |
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(Received 22 May 2003;
accepted after revision 23 June 2003;
first published online 24 June 2003)
Corresponding author I. Findlay: CNRS UMR 6542, Faculté des Sciences, Université de Tours, Parc de Grandmont, 37200 Tours, France. Email: findlay{at}univ-tours.fr
Introduction
Mutagenesis, chimera constructions and differential subunit expression have provided original insight into the processes of activation, permeation and inactivation of L-type Ca2+ channels (ICaL). The fundamental role of calmodulin mediating the process of Ca2+-dependent inactivation has been defined (Qin et al. 1999; Anderson, 2001) along with the action of calcium-calmodulin-dependent kinase II (Maier & Bers, 2002). The ensemble of this data accounts for variation in the behaviour of ICaL due to the expression in different tissues of splice variants, long and short forms of the 
1c subunit and combinations with different ß subunits. On the other hand, physiological modulation of the behaviour of ICaL by the means of phosphorylation via protein kinase A (PKA) which underlies sympathetic, parasympathetic and purinergic regulation of the Ca2+ current (McDonald et al. 1994; Kamp & Hell, 2000) has been less amenable to explanation by the methods of in vitro reconstruction. Few have succeeded in the reconstitution of the response of ICaL to stimulation via PKA (Gao et al. 1997; Naguro et al. 2001). Part of this problem has been found to be the assemblage of all of the elements required to affirm this reaction (Gao et al. 1997). The rest has been in determining what actually is or are the reactions of ICaL to agonist stimulation.
It is commonly held that the effect of ß-adrenergic stimulation of ICaL is the increase in amplitude of the whole-cell current arising from an increase in the availability of the channels as well as an increase in their probability of opening; the voltage dependence of activation and inactivation of ICaL are shifted to more negative voltages (McDonald et al. 1994; Bers & Perez-Reyes, 1999). Inactivation of ICaL occurs via processes associated with membrane voltage and the increase in intracellular Ca2+. Initially, the relative extents of these two mechanisms was disputed (Kass & Sanguinetti, 1984; Mentrard et al. 1984; Lee et al. 1985; Hadley & Hume, 1987; Argibay et al. 1988). Today it is generally assumed that the dominant character determining the rapid decay of ICaL is inactivation consequent to the influx of Ca2+ (Linz & Meyer, 1998; Sun et al. 2000). The increase of inactivation following ß-adrenergic stimulation can then readily be understood as a consequence of enhanced Ca2+ influx upon increased channel activity.
The physical mechanism of inactivation of ICaL is not known. In Ca2+ channels there is no obvious equivalent of the ‘ball-and-chain’ or rearrangement of the pore-lining segments which produce inactivation of voltage-gated Na+ or K+ channels (Antz & Fakler, 1998; Cantrell & Catterall, 2001). It is not known whether the processes of voltage-dependent inactivation and Ca2+-dependent inactivation have the same physical endpoint or whether they represent different mechanisms?
Recently a series of studies of ICaL in native cardiac myocytes have opened new perspectives upon the old problem of voltage- and Ca2+-dependent inactivation (Mitarai et al. 2000; Findlay, 2002a,b,c,d). This short review will summarize these novel ideas and attempt to integrate them into a simple framework. This framework is the switching on and the switching off of rapid voltage-dependent inactivation of the individual Ca2+ channel.
Voltage-dependent inactivation
The classical view of voltage-dependent inactivation (VDI) of ICaL is that it is slow and accelerates only slightly with depolarization (Bechem & Pott, 1985; Fukushima & Hagiwara, 1985; Matsuda, 1986). This vision resulted from experiments that were conducted under conditions that were the equivalent of ß-adrenergic stimulation (see below). When attention was paid to record ICaL under basal conditions VDI strongly increased with progressive depolarization (Fig. 1) and was rapid at positive membrane potentials (Mitarai et al. 2000; Findlay, 2002a,d).
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f
30 ms and s300 ms) which was dominated by the rapid phase of inactivation.
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Sympathetic and parasympathetic regulation of ICaL in cardiac muscle follows activation of adenylate cyclase and PKA (Kamp & Hell, 2000). There are several prospective sites for the action of PKA upon 1C and ß2 subunits (Bunemann et al. 1999) and the close association of PKA with the Ca2+ channel in a supramolecular complex is required for in vitro reconstitution of the ß-adrenergic response (Gao et al. 1997). The isolation of VDI following ß-adrenergic stimulation has not been easy. The effect of ß-adrenergic stimulation upon the apparently voltage-dependent inactivation of ICaL carried by Ba2+ or Sr2+ has given rather mixed results with clear indications of the contribution of an ion-dependent process (Tiaho et al. 1991; Ferreira et al. 1997; Findlay, 2002a). On the other hand, following ß-adrenergic stimulation ICaL carried by Na+ clearly retains the character of VDI without ion-dependent inactivation (Mitarai et al. 2000; Findlay, 2002a). In these circumstances VDI is slow and shows little development with depolarization. These recent results therefore correspond to the classical view of VDI (Bechem & Pott, 1985; Fukushima & Hagiwara, 1985; Matsuda, 1986) which for diverse reasons were conducted in fact under experimental conditions that were likely to lead to activation of PKA.
Analysis of the effects of agonists upon VDI (Mitarai et al. 2000; Findlay, 2002c) revealed that the number of ion channels which showed rapid VDI was reduced by the ß-adrenergic agonist isoprenaline in a dose-dependent manner (Fig. 4). At the same time the number of ion channels which did not show VDI was increased. At each dose of isoprenaline, the addition of the muscarinic agonist carbachol increased the number of channels which showed rapid VDI and reduced the number of channels which did not show VDI (Findlay, 2002c). There was clearly a reciprocal relationship between the number of channels which did show rapid VDI and the number of channels which did not show rapid VDI. Since these ß-adrenergic and muscarinic agonists are considered to act upon the Ca2+ channels by, respectively, increasing and decreasing their phosphorylation via PKA, this would suggest that phosphorylation turns off or otherwise prevents the mechanism of rapid VDI. This simple switch would convert ion channels which did show rapid VDI into channels which did not show VDI.
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In historical terms, it is not the drastic reduction of VDI of ICaL in cardiac myocytes which is evoked by ß-adrenergic stimulation that would be considered to be an unusual result. Though it should be mentioned that this effect of agonist modulation of a voltage-gated ion channel is unique to ICaL. Agonist modulation of voltage-gated Na+ and K+ channel currents is confined to shifting activation and inactivation curves along the voltage axis (Cantrell & Catterall, 2001). They do not result in the reduction of the minimum of the inactivation curve (Fig. 4A). The novel aspect of this analysis of VDI of ICaL in cardiac myocytes is the discovery of rapid VDI under basal conditions in the absence of agonists (Findlay, 2002a,b,c,d). The decay of ICaL carried by Ca2+ in cardiac myocytes is rapid and when it was thought that VDI was slow, it was inferred that Ca2+-dependent inactivation was the dominant physiological mechanism of inactivation (Linz & Meyer, 1998; Sun et al. 2000). This conclusion is called into question with the discovery of rapid VDI.
Ca2+-dependent Inactivation
Ca2+-dependent inactivation (CDI) of ICaL is mediated by the interaction of the Ca2+-binding protein calmodulin with the proximal region of the cytoplasmic C-terminus of the 1C subunit of the Ca2+ channel (Anderson, 2001; Maier & Bers, 2002). Calmodulin is attached to the Ca2+ channel in the presence of basal intracellular Ca2+ concentrations (Erickson et al. 2001; Pitt et al. 2001). An increase in intracellular Ca2+ activates calmodulin which reorientates its attachments and in consequence is thought to alter the 3D structure of the C-terminus (Petersen et al. 2000). In an unknown manner, this procedure provokes inactivation of ICaL. The implication of calmodulin with the process of CDI of ICaL has several interesting consequences. The first of these is that calmodulin is not selective and there is no obligation for Ca2+ which has entered via a Ca2+ channel to provoke inactivation. Any increase of Ca2+ in the vicinity of the internal surface of the channel will suffice to trigger CDI irrespective of whether the channel has opened or not. Thus Ca2+-induced Ca2+-release (CICR) from the cardiac sarcoplasmic reticulum can cause CDI (Adachi-Akahane et al. 1996; Sham, 1997). The opening of a neighbouring Ca2+ channel can cause CDI (Imredy & Yue, 1992). The triggering of CICR by chemical means can cause CDI (Lipp et al. 1987; Adachi-Akahane et al. 1996). The photolytic release of Ca2+ from intracellular caged compounds can cause CDI (Hadley & Lederer, 1991; Bates & Gurney, 1993). In cardiac myocytes it is not clear to what extent Ca2+ which enters via a given Ca2+ channel causes CDI of that channel. Otherwise it would be difficult to account for the significant effects of CICR upon CDI within the local-control domain (Stern, 1992; Wier et al. 1994) which suggests that while sufficient Ca2+ can enter via the surface Ca2+ channel to provoke CICR, this is insufficient to locally provoke CDI. Also, in cells which lack the geometry of close association between surface membrane and junctional sarcoplasmic reticulum, CDI is related more closely to the overall cell current density of ICaL rather than the driving force for Ca2+ entry via the single channel (Argibay et al. 1988). The second point which arises from the association of calmodulin with the process of CDI is that the interaction between Ca2+ and calmodulin is readily reversible and entirely dependent upon the local Ca2+ concentration. But it is dogma that inactivation of voltage-gated ion channels is an absorptive state that requires a period at a hyperpolarized potential to recover (Imredy & Yue, 1994) while several studies have shown that CDI might be reversible without repolarization (Sipido et al. 1995; Brette et al. 2003). It was therefore in the context of this complexity of the kinetics and sources of CDI that recent studies which wished to evaluate the relative contributions of CDI and VDI to the decay of ICaL in native cardiac myocytes chose to block CICR with ryanodine (Findlay, 2002a,c). In this manner, CDI where it occurred would result entirely from the influx of Ca2+ through sarcolemmal Ca2+ channels.
Two methods were used to assess the relative contributions of CDI and VDI in isolated cardiac myocytes. The first compared the decay of ICaL carried by Ca2+ with that of ICaL carried by Ba2+, Sr2+ and Na+ (Findlay, 2002a). The second utilized the technique developed by Hadley & Hume (1987) which enables the recording of ICaL in the absence of cation influx when ICaL is blocked by extracellular Mg2+ (Findlay, 2002b). In basal conditions at positive membrane potentials the development of inactivation followed a biphasic time course and there was little or no difference between the initial rapid phase of inactivation of ICaL when this resulted from the influx of Ca2+, Ba2+, Sr2+, Na+ or no ion flux (Figs 1A and 2C). The second, slow phase of inactivation was less when ICaL was carried by Ca2+ (Fig. 1A). These results quite clearly showed that the initial rapid phase of inactivation of ICaL was independent of CDI and therefore due to VDI. This represents the reverse of the traditional description of fast decay of ICaL due to CDI and slow decay of ICaL due to VDI (Adams & Tanabe, 1997; Ferreira et al. 1997; Sun et al. 1997). At negative membrane potentials the distinction between the decay of ICaL carried by Ca2+ and the other cations was larger (Fig. 1A) and it was clear that CDI did play an important role in determining the decay of ICaL (Fig. 1B). When these experiments were repeated following maximal ß-adrenergic stimulation with isoprenaline ICaL carried by Ca2+ decayed more rapidly than ICaL carried by the other cations at all voltages (Fig. 3A). In these circumstances CDI dominated the decay of ICaL (Figs 3B and 4C).
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Conclusions and perspectives
It is not necessary to look for complicated explanations for the variation of the contributions of VDI and CDI to the decay of ICaL under a range of physiological conditions. Physiological modulation of inactivation of ICaL is proposed to act at a single point, the triggering of rapid voltage-dependent inactivation. This is turned on with depolarization, and turned off by phosphorylation. When it is on, CDI is ineffective; when it is off, CDI is effective. The graded influence of VDI and CDI and the effects of ß-adrenergic and muscarinic agonists are then a consequence of the variation in the number of individual ion channels which show VDI. It is proposed that at the level of the single L-type Ca2+ channel rapid VDI will either occur or not. That single Ca2+ channels are capable of switching between rapid VDI and no inactivation has already been shown for a neuronal N-type Ca2+ channel (Plummer & Hess, 1991). The probability of this occurring in the L-type Ca2+ channel would increase with increasing depolarization. Since a channel which has already been inactivated by voltage cannot show inactivation which is caused by Ca2+ it is clear that the on–off switch for the occurrence of fast VDI determines the visible contribution of Ca2+ to the overall time course of decay of ICaL. Thus, as the number of channels which adopt rapid VDI increases, the number of channels which are inactivated by Ca2+ decreases. The prevention of fast VDI by phosphorylation of the channel either at the 1C or at the ß2 subunit will then permit CDI.
It seems likely that CDI is a process that has a certain latency. This does not necessarily arise from the interaction of calmodulin with the C-terminus of the channel, in particular since calmodulin can be expected to be tethered to the channel under all physiological conditions (Erickson et al. 2001; Pitt et al. 2001). But the rise in ‘fuzzy space’ Ca2+ to the level required to trigger the transformation of calmodulin might require a certain time, in particular since Ca2+ from several sources is known to provoke CDI and may be required to provoke CDI (Imredy & Yue, 1994; Adachi-Akahane et al. 1996).
The physiological consequences of these observations reside in the observation of the dominance of VDI at positive membrane potentials under basal conditions which is replaced by the dominance of CDI following ß-adrenergic stimulation (Findlay, 2002b). These results predict that should there be an error in the process of CDI this would have little effect upon ICaL and its contribution to the action potential under basal conditions. On the other hand, this would cause a drastic slowing of the decay of ICaL and probably massive elongation of the action potential following ß-adrenergic stimulation. Alseikhan et al. (2002) have expressed mutant Ca2+-insensitive calmodulin in isolated cardiac myocytes. The action potentials recorded from these cells were drastically increased. This clearly illustrates the importance that CDI could have to limit the contribution of ICaL to the electrophysiology of cardiac myocytes. These experiments were conducted in the absence of agonists and thus presumably under basal conditions, which would contradict the importance of VDI which is suggested here. But it was noted that the adenovirus infection technique by itself evoked an increase in the density of ICaL (Alseikhan et al. 2002). It is therefore possible that PKA was activated in these cells. It remains to be seen whether, with a normal basal density of ICaL, the duration of the cardiac action potential would have been elongated by the expression of mutated calmodulin.
It is interesting also to consider that abolition of the process of VDI of ICaL might be without obvious consequence upon the electrophysiology of the cardiac myocyte. VDI is already essentially abolished by ß-adrenergic stimulation under which circumstances rapid decay of ICaL is undertaken by CDI (Fig. 4C: Findlay, 2002b). There is therefore no reason to suppose that this would not also occur should VDI be impeded under basal conditions. In any case, CDI already contributes to the decay of ICaL under basal conditions at negative membrane potentials where VDI has little effect (Findlay, 2002a).
Notwithstanding that chimera constructions of the 1 subunit and the expression of different ß subunits of voltage-gated Ca2+ channels have been able to indicate regions of the channel that can be involved in VDI (Stotz & Zamponi, 2001b), none have had to account for the physiological modulation of this process. Three sites upon the L-type Ca2+ channel are known to be phosphorylated by PKA: two sites upon the ß2 subunit and one site distal to the calmodulin binding regions of the C-terminus of the 1C subunit (Puri et al. 1997). Although it is now clear that the proximal region of the C-terminus of the 1C subunit is responsible for CDI (Erickson et al. 2001; Pitt et al. 2001), it is not known how this is achieved and it is not known what effect PKA-induced phosphorylation of this region (Puri et al. 1997) has upon either CDI or VDI. None of the experiments conducted by either Mitarai et al. (2000) or Findlay (2002a,b,c,d) suggest that CDI is a process that could be influenced directly by phosphorylation of the Ca2+ channel.
ß2 subunits which influence, amongst other things, the rate of inactivation of Ca2+ channels (Birnbaumer et al. 1998) are attached to the 1C subunit at the I–II intracellular linker (Pragnell et al. 1994). This linker has been suggested to be responsible for VDI via a ‘hinged-lid’ mechanism which would occlude the internal vestibule of the channel pore (Stotz & Zamponi, 2001a). If movement of the I–II linker and attached ß2 subunit was responsible for the mechanism of VDI it would not be difficult to imagine that phosphorylation of the ß2 subunit might physically affect this process. There may be analogy to be drawn with the effect of phosphorylation of the N-terminal inactivation particle of voltage-gated K+ channels altering its configuration and affinity for the vestibule receptor (Covarrubias et al. 1994; Antz et al. 1999). Alternatively, phosphorylation or dephosphorylation of the ß2 subunit might be responsible for dissociation of the ß2 subunit from the I–II linker (Bichet et al. 2000; Restituito et al. 2001). Finally, it is not to be excluded that the distal region of the C-terminus of 1C which is truncated by post-translational proteolysis, but which can remain attached to the channel complex (Gerhardstein et al. 2000; Gao et al. 2001) may play a role which could be influenced by phosphorylation of Ser 1928 (Gao et al. 1997).
In conclusion, it is clear that the concept of physiological modulation of VDI of ICaL (CaV1.2) which has arisen from studies of the native channel in its physiological context poses some direct questions that remain to be answered with the tools of molecular biology and mutagenesis. The description of a very loose, open and flexible structure of a voltage-gated K+ channel (Jiang et al. 2003a,b) may provide impetus towards the decryption of the processes of activation and inactivation of the more complex supramolecular structure of the mammalian Ca2+ channel. This review has concentrated attention upon the behaviour of ICaL in cardiac myocytes in the absence of CICR. The influence of CICR upon the inactivation of ICaL in native cardiac myocytes is an important component of the physiology of the regulation of the cardiac action potential. But this geometric arrangement is particular to cardiac myocytes. By concentrating attention upon the influence of Ca2+ influx upon inactivation of ICaL it is hoped that the concepts which have been developed here from work upon cardiac myocytes may find application to a wider range of tissues.
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  D. B. Tikhonov and B. S. Zhorov Molecular Modeling of Benzothiazepine Binding in the L-type Calcium Channel J. Biol. Chem., June 20, 2008; 283(25): 17594 - 17604. [Abstract] [Full Text] [PDF]
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 C. F. Barrett and R. W. Tsien The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels PNAS, February 12, 2008; 105(6): 2157 - 2162. [Abstract] [Full Text] [PDF]
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 D.-D. Feng, Y.-F. Zhao, Z.-Q. Luo, D. J Keating, and C. Chen Linoleic acid induces Ca2+-induced inactivation of voltage-dependent Ca2+ currents in rat pancreatic {beta}-cells J. Endocrinol., February 1, 2008; 196(2): 377 - 384. [Abstract] [Full Text] [PDF]
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 Z. I. Zhu and C. E. Clancy L-type Ca2+ channel mutations and T-wave alternans: a model study Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3480 - H3489. [Abstract] [Full Text] [PDF]
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 S. J. Liu Inhibition of L-type Ca2+ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes Am J Physiol Cell Physiol, November 1, 2007; 293(5): C1594 - C1604. [Abstract] [Full Text] [PDF]
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 G. M. Faber and Y. Rudy Calsequestrin mutation and catecholaminergic polymorphic ventricular tachycardia: A simulation study of cellular mechanism Cardiovasc Res, July 1, 2007; 75(1): 79 - 88. [Abstract] [Full Text] [PDF]
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 G. M. Faber, J. Silva, L. Livshitz, and Y. Rudy Kinetic Properties of the Cardiac L-Type Ca2+ Channel and Its Role in Myocyte Electrophysiology: A Theoretical Investigation Biophys. J., March 1, 2007; 92(5): 1522 - 1543. [Abstract] [Full Text] [PDF]
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 A. Olypher, G. Cymbalyuk, and R. L. Calabrese Hybrid Systems Analysis of the Control of Burst Duration by Low-Voltage-Activated Calcium Current in Leech Heart Interneurons J Neurophysiol, December 1, 2006; 96(6): 2857 - 2867. [Abstract] [Full Text] [PDF]
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 R. Rizzuto and T. Pozzan Microdomains of Intracellular Ca2+: Molecular Determinants and Functional Consequences Physiol Rev, January 1, 2006; 86(1): 369 - 408. [Abstract] [Full Text] [PDF]
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 D. B. Halling, P. Aracena-Parks, and S. L. Hamilton Regulation of Voltage-Gated Ca2+ Channels by Calmodulin Sci. Signal., December 20, 2005; 2005(315): re15 - re15. [Abstract] [Full Text] [PDF]
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