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L-Type Calcium Channels: The Low Down
Diane Lipscombe, Thomas D. Helton and Weifeng Xu
J Neurophysiol
92:2633-2641, 2004.
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J Neurophysiol 92: 2633–2641, 2004;10.1152/jn.00486.2004.
L-Type Calcium Channels: The Low Down Diane Lipscombe, Thomas D. Helton, and Weifeng Xu
Department of Neuroscience, Brown University, Providence, Rhode Island 02912
Submitted 9 May 2004; accepted in final form 5 June 2004 Lipscombe, Diane, Thomas D. Helton, and Weifeng Xu. L-type
agonists and antagonists has proved critical for their identifi- calcium channels: The low down. J Neurophysiol 92: 2633–2641, cation in physiological assays and also for their biochemical 2004; 10.1152/jn.00486.2004. L-type calcium channels couple mem- isolation (Kanngiesser et al. 1988). Biochemical purification of brane depolarization in neurons to numerous processes including gene the dihydropyridine receptor from skeletal muscle was the expression, synaptic efficacy, and cell survival. To establish the essential step in cloning the first voltage-gated calcium channel contribution of L-type calcium channels to various signaling cascades, (Tanabe et al. 1987). Sequence information from this landmark investigators have relied on their unique pharmacological sensitivityto dihydropyridines. The traditional view of dihydropyridine-sensitive study was then used to screen for and clone Ca 1.2 and Ca 1.3 L-type calcium channels is that they are high-voltage–activating and cDNAs (Biel et al. 1990; Hui et al. 1991; Koch et al. 1990; have slow activation kinetics. These properties limit the involvement Mikami et al. 1989; Perez-Reyes et al. 1990; Williams et al.
of L-type calcium channels to neuronal functions triggered by strong 1992). Functional analyses of cloned channels, primarily of and sustained depolarizations. This review highlights literature, both Ca 1.2, were generally consistent with native cardiac L-type long-standing and recent, that points to significant functional diversity channels and the following criteria evolved for their identifi- among L-type calcium channels expressed in neurons and other excitable cells. Past literature contains several reports of low-voltage– 1) Activation by strong depolarizations (high-voltage–acti- activated neuronal L-type calcium channels that parallel the unique vated [HVA]).
properties of recently cloned Ca 1.3 L-type channels. The fast kinet- 2) High sensitivity to dihydropyridine agonists and antago- ics and low activation thresholds of Ca 1.3 channels stand in stark contrast to criteria currently used to describe L-type calcium channels.
A more accurate view of neuronal L-type calcium channels encom- 3) Relatively slow activation kinetics.
passes a broad range of activation thresholds and recognizes their 4) Calcium-dependent inactivation with little voltage-de- potential contribution to signaling cascades triggered by subthreshold pendent inactivation (long-lasting).
5) Large single-channel conductance.
However, a substantial body of evidence points to hetero- geneity among neuronal L-type calcium channels that has until L-type calcium channels regulate numerous recently received little attention. This review highlights recent studies of cloned channels, as well as long-standing studies of L-type calcium channels are perhaps the best characterized native L-type channels, that point to significant deviations from of the voltage-gated calcium channels. They were first recog- criteria listed above in the properties of L-type channels.
nized as essential for coupling excitation to contraction inskeletal, cardiac, and smooth muscle cells (Beam et al. 1989; Ca 1 genes encode L-type calcium channels Franzini-Armstrong and Protasi 1997; Reuter 1985; Schneider and Chandler 1973; Tanabe et al. 1990). L-type calcium Identifying the genes that encode core Ca ␣ subunits of channels are also expressed in neurons and endocrine cells voltage-gated calcium complexes has led to a comprehensive where they regulate a multitude of processes including secre- sequence-based classification scheme (Fig. 1). When se- tion of neurohormones and transmitters, gene expression, quences are compared, voltage-gated calcium channels fall into mRNA stability, neuronal survival, ischemic-induced axonal three main groups: Ca 1 (L-type), Ca 2 (P-type, N-type, and injury, synaptic efficacy, and the activity of other ion channels R-type), and Ca 3 (T-type) (Ertel et al. 2000; Lipscombe (Ashcroft et al. 1994; Bading et al. 1993; Bean 1989; Charles 2002b). In general, these gene families correspond to the et al. 1999; Christie et al. 1997; De Koninck and Cooper 1995; subtypes of calcium channels defined by functional and phar- Deisseroth et al. 1998; Dunlap et al. 1995; Finkbeiner and macological criteria. Ca 1 and Ca 2 genes are more closely Greenberg 1998; Fuchs 1996; Galli et al. 1995; Heidelberger related to each other when compared with Ca 3 genes. Ca 3 and Matthews 1992; Kamsler and Segal 2003; Lei et al. 2003; T-type channels possess certain functional properties that set Marrion and Tavalin 1998; Marshall et al. 2003; Murphy et al.
them apart from other voltage-gated calcium channels (Perez- 1991; Norris et al. 1998; Ouardouz et al. 2003; Sand et al.
Reyes et al. 1998). Low-voltage–activating calcium current 2001; Schorge et al. 1999; Shinnick-Gallagher et al. 2003; typically marks the presence of Ca 3 T-type channels. How- Smith et al. 1993; Tachibana et al. 1993; Thaler et al. 2001; ever, as we will discuss, this property is shared by Ca 1.3, a Thibault et al. 2001; Weisskopf et al. 1999; Wiser et al. 1999; member of the Ca 1 gene family, and thus should not be Zhang and Townes-Anderson 2002). The unique pharmacolog- considered unique to Ca 3 (Avery and Johnston 1996; Kos- ical sensitivity of L-type calcium channels to dihydropyridine chak et al. 2001; Lipscombe 2002a; Platzer et al. 2000; Scholze Address for reprint requests and other correspondence: D. Lipscombe, The costs of publication of this article were defrayed in part by the payment Department of Neuroscience, Brown University, 190 Thayer Street, Provi- of page charges. The article must therefore be hereby marked "advertisement" dence, RI 02912 (E-mail: diane_lipscombe@brown.edu).
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
0022-3077/04 $5.00 Copyright 2004 The American Physiological Society


D. LIPSCOMBE, T. D. HELTON, AND W. XU Schultz et al. 1993; Soldatov 1992; Takimoto et al. 1997;Welling et al. 1997). This channel opens as the membranepotential depolarizes beyond about ⫺30 mV. Ca 1.2 channels help define the shape of the action potential in cardiac andsmooth muscle. These channels function primarily as calciumion channels and, unlike Ca 1.1 of skeletal muscle, calcium flow through Ca 1.2 is an essential step in initiating the signaling cascade that leads to cardiac and smooth musclecontraction (Reuter et al. 1988; Tanabe et al. 1990). In neuronsCa 1.2 channels are thought to couple membrane depolariza- tion to regulation of gene expression (Dolmetsch et al. 2001;Weick et al. 2003).
The Ca 1.3 gene, formerly ␣ , is expressed in many of the same cells that express Ca 1.2. In neurons, Ca 1.2 and Ca 1.3 are often found in the same general neuronal compartments,particularly dendrites, but their subcellular distributions appear Ca ␣ subunit gene tree. Full-length amino acid sequences for all distinct (Hell et al. 1993; Westenbroek et al. 1998). Ca 1.3 has 10 human Ca ␣ genes were aligned using a branch and bound tree search with been found to co-localize with the small conductance calcium- maximum parsimony (Genetic Computer Group, paupsearch and paupdisplay activated potassium channel (Bowden et al. 2001). Ca 1.3 is programs). Accession numbers for sequences used are: Ca 1.1, L33795; Ca 1.2, AJ224873; Ca 1.3, M76558; Ca 1.4, AJ224874; Ca 2.1, AB035727; also expressed in pancreatic beta cells, neuroendocrine cells, Ca 2.2, M94173; Ca 2.3, L27745; Ca 3.1, AF190860; Ca 3.2, AF05196; photoreceptors, amacrine cells, and hair cells of the inner ear Ca 3.3, AF211189. Confidence values for each node were determined by where it mediates synaptic transmission (Habermann et al.
bootstrap analysis. All unlabeled nodes represent 100% confidence. Represen- 2003; Ihara et al. 1995; Kollmar et al. 1997a,b; Liu et al. 2004; tation was rooted using the midpoint method. Scale bar represents 1 substitu-tion per 100 amino acids. This tree is essentially the same when we exclude the Morgans 1999; Morgans et al. 1998; Platzer et al. 2000; Russo variable intracellular loops (I–II, II–III) and N- and C-termini (Lipscombe et al. 2003; Safa et al. 2001; Scholze et al. 2001; Seino et al.
2002b). Our analysis indicates a stronger similarity between Ca 1.3 and 1992; Taylor and Morgans 1998). In the heart, Ca 1.3 is Ca 1.4 genes compared with that of other published Ca gene trees (Ertel et present in atrial tissue where it contributes to pacemaking al. 2000). If we just align sequences of the 4 Ca 1 genes the confidence value (Mangoni et al. 2003; Platzer et al. 2000; Takimoto et al. 1997; at the Ca 1.3–Ca 1.4 node increases to 100%.
Zhang et al. 2002), but not in ventricular muscle that expresses et al. 2001; Xu and Lipscombe 2001). Until recently, all members of Ca 1 and Ca 2 gene families were considered The Ca 1.4 gene, formerly ␣ , is expressed primarily in high-voltage–activated. Ca 1 channels are distinguishable retina and is linked to a rare human disorder, stationary night from Ca 2 channels primarily by their unique pharmacology.
blindness (Bech-Hansen et al. 1998; Strom et al. 1998). Ca 1.4 Ca 1 channels are sensitive to dihydropyridine agonists and is found at synaptic terminals of retinal bipolar cells, and RNA antagonists, but are not blocked by ␻-aga IVA or ␻-conotoxin encoding Ca 1.4 has also been PCR amplified from dorsal root GVIA, which inhibit Ca 2.1 and Ca 2.2 channels, respectively ganglia (Berntson et al. 2003; Murakami et al. 2001). Interest- (Bean 1991; Cruz et al. 1987; McIntosh et al. 1999; Mintz et al.
ingly, the Ca 1.4 gene sequence is more homologous to 1992). However, as we will discuss, dihydropyridine antago- Ca 1.3, based on comparisons among available Ca nists do not completely inhibit all L-type channels.
Four mammalian Ca 1 genes encode L-type L-type calcium channels are functionally diverse calcium channels Analyses of Ca 1 clones in various heterologous expression Four Ca 1 genes are present in the human genome, referred systems have provided compelling data that L-type calcium to as Ca 1.1–1.4 (Fig. 1). The Ca 1.1 gene, formerly ␣ , is channels are a functionally heterogeneous family.
expressed in skeletal muscle. Ca 1.1 directly links to ryano- 1) Not all L-type calcium channels require strong depolar- dine receptors in the sarcoplasmic reticulum (Flucher and izations for activation; Ca 1.3 and Ca 1.4 channels have low Franzini-Armstrong 1996). Ca 1.1 primarily acts as a voltage sensor, coupling depolarization to release of intracellular cal- 2) L-type calcium channels are not all inhibited equally well cium by activating the ryanodine receptor. The influx of by dihydropyridine antagonists; Ca 1.3 and Ca 1.4 L-type calcium through the ion pore of Ca 1.1 during gating is channels are significantly less sensitive compared with Ca 1.2.
secondary to its primary role as a voltage sensor (Schwartz et 3) Activation kinetics of L-type calcium channels vary.
al. 1985). The coupling between depolarization and channel Ca 1.3 channels activate with fast kinetics, whereas Ca 1.1 opening is inefficient; Ca 1.1 channels open with slow kinetics channels open slowly.
(Almers and Palade 1981; Rios and Brum 1987; Tanabe et al.
4) Certain Ca 1.4 L-type channels do not exhibit calcium- dependent inactivation. Furthermore, in physiological solu- The Ca 1.2 gene, formerly ␣ , is expressed in a variety of tions that contain calcium, L-type calcium channels that do cells including ventricular cardiac muscle, smooth muscle, undergo calcium-dependent inactivation are not long lasting.
pancreatic cells, fibroblasts, and neurons (Diebold et al. 1992; 5) Most L-type calcium channels have relatively large sin- Koch et al. 1990; Mori et al. 1993; Perez-Reyes et al. 1990; gle-channel conductances when isotonic barium is the charge J Neurophysiol • VOL 92 • NOVEMBER 2004 • www.jn.org L-TYPE CALCIUM CHANNELS carrier. However, analyses of single Ca 1.3 and Ca 1.4 chan- The Ca 1.3 knockout mice, however, renewed interest and nels are lacking.
provided compelling evidence that the Ca 1.3 gene encodes L-type calcium channels with unusual properties (Mangoni et Skeletal muscle Ca 1.1 and cardiac Ca 1.2 L-type channels al. 2003; Platzer et al. 2000; Zhang 2002). At the behavioral are functionally distinct level, mice lacking the L-type Ca 1.3 gene experience signif- icant sinoatrial node dysfunction characterized by sinus brady- Although the first Ca ␣ subunit to be cloned, Ca 1.1 cardia. This unanticipated role for Ca 1.3 in pacemaking resisted functional reconstitution in nonmuscle, heterologous implies that these L-type calcium channels are important in expression systems (Tanabe et al. 1987). Successful expression mediating subthreshold depolarizations in the sinoatrial node.
of Ca 1.1 was eventually achieved using embryonic muscle The absence of a low-threshold activating calcium current in from dysgenic mice. In a series of classic experiments, Numa, sinoatrial node cells of Ca 1.3 ⫺/⫺ mice confirmed this Beam, and colleagues, rescued excitation– contraction cou- hypothesis (Zhang 2002). Hearing loss and the absence of a pling as well as L-type calcium channel currents in dysgenic low-threshold activating calcium current in hair cells from muscle by expressing Ca 1.1 cDNA in these cells (Adams et these mice are consistent with prominent expression of Ca 1.3 al. 1990; Tanabe et al. 1988). Ca 1.1 currents were small and in inner hair cells of the cochlea (Kollmar et al. 1997b; Platzer activated with slow kinetics, properties consistent with native et al. 2000). The functional properties of Ca 1.3 clones iso- L-type currents in skeletal muscle. As in skeletal muscle, lated from neurons and endocrine cells, more recently, confirm contraction depended on the mobilization of intracellular cal- that Ca 1.3 L-type channels activate at subthreshold voltages cium stores. Ca 1.2 could also reconstitute excitation– contrac- (Koschak et al. 2001; Platzer et al. 2000; Safa et al. 2001; Xu tion coupling in dysgenic muscle, but the features were dis- and Lipscombe 2001).
tinctly cardiac-like. In this case, calcium flux across the mem-brane through Ca 1.2 channels was essential to trigger muscle Ca 1.3 L-type channels activate at relatively hyperpolarized contraction (Tanabe et al. 1990). Ca 1.2 channels opened with rates that were significantly faster compared with Ca 1.1.
Chimeric analyses demonstrated that sequence differences in Figure 2 illustrates that Ca 1.2 and Ca 1.3 channels have the II–III intracellular linker region of Ca 1.1 and Ca 1.2 very different activation thresholds. The Ca 1.2 and Ca 1.3 genes imparted the skeletal or cardiac muscle form of excita- clones used were isolated from neuronal tissue, expressed in tion– contraction coupling. In subsequent experiments Beam tsA201 cells, and recorded under identical conditions. With and colleagues demonstrated that sequence differences in the physiological concentrations of extracellular calcium, Ca 1.3 domain IS3–IS4 linkers of Ca 1.1 and Ca 1.2 genes deter- channels start to activate at about ⫺55 mV, a voltage that is mined the gating phenotypes of these two L-type calcium approximately 20 –25 mV more hyperpolarized as compared channels (Nakai et al. 1994). The slow gating phenotype of with Ca 1.2. Low-threshold activation is a prominent feature Ca 1.1 channels was transferred to Ca 1.2 by swapping in the of all Ca 1.3 clones isolated recently, independent of tissue of IS3–IS4 linker of Ca 1.1. Variations in S3–S4 linker se- origin and of auxiliary subunits (Koschak et al. 2001; Safa et quences among other voltage-gated ion channel gene families al. 2001; Scholze et al. 2001; Xu and Lipscombe 2001). Why and their splice isoforms are similarly important in modulating was this unique and salient feature of Ca 1.3 not highlighted in channel gating kinetics (Lipscombe 2002b; Mathur et al. 1997; earlier studies (Bell et al. 2001; Ihara et al. 1995; Williams et Tang and Papazian 1997).
al. 1992)? The most likely explanation relates to the use of highconcentrations of extracellular barium and calcium in these Ca 1.2 and Ca 1.3 L-type channels are functionally distinct studies to compensate for low expression levels. Under these conditions, Ca 1.3 channels would have activated at signifi- With the exception of skeletal muscle and perhaps retina, all cantly more depolarized voltages as a result of surface charge excitable cells express one or both Ca 1.2 and Ca 1.3 genes.
screening (Frankenhaeuser and Hodgkin 1957; Hille 2001).
The products of these genes constitute the major fraction of Indeed, when we studied Ca 1.3 L-type currents under similar L-type calcium channels in mammals (Hell et al. 1993; Ludwig conditions, 40 mM extracellular barium, the current–voltage et al. 1997; Takimoto et al. 1997; Williams et al. 1992). Until relationship shifted into the range of a high-voltage–activated recently, the prevailing image of the neuronal L-type calcium L-type calcium channel (Xu and Lipscombe 2001). Additional channel was of a high-voltage-activated, slowly activating factors such as interactions with other subunits, modulation by channel with high sensitivity to dihydropyridines (Ertel et al.
second-messenger signaling cascades, and alternative splicing 2000; Hille 2001). These features have developed primarily have the potential to influence channel properties (Birnbaumer from biophysical analyses of heterologously expressed Ca 1.2 et al. 1998; Lipscombe 2002b; Scholze et al. 2001). However, L-type calcium channels (Altier et al. 2001; Bourinet et al.
low-voltage activation appears to be a salient feature of 1994; Charnet et al. 1994; de Leon et al. 1995; Ivanina et al.
Ca 1.3-containing channels (Koschak et al. 2001; Michna et 2000). Although Ca 1.3 was first cloned in the early 1990s, al. 2003; Safa et al. 2001; Scholze et al. 2001; Xu and low expression levels in heterologous systems limited electro- Lipscombe 2001).
physiological studies of this L-type calcium channel (Hui et al.
1991; Williams et al. 1992). Aside from a report that Ca 1.3 Ca 1.3 L-type channels are only partially inhibited L-type channels could be reversibly inhibited by the N-type calcium channel blocker ␻-conotoxin GVIA (Williams et al.
1992), a result that has not been confirmed (Xu and Lipscombe All L-type calcium channels studied to date are sensitive to 2001), Ca 1.3 channels were not considered unique.
dihydropyridine antagonists and agonists. However, Ca 1.3- J Neurophysiol • VOL 92 • NOVEMBER 2004 • www.jn.org



D. LIPSCOMBE, T. D. HELTON, AND W. XU currents that resemble the R-type current of many neurons(Foehring et al. 2000; Randall and Tsien 1995; Tottene et al.
1996; Yasuda et al. 2003; Zhuravleva et al. 2001).
Ca 1.3 L-type channels open with rapid kinetics L-type calcium channels in neurons are typically thought of as slowly activating (Mermelstein et al. 2000; Yasuda et al.
2003). If true, this property limits the involvement of L-typecalcium channels to signaling pathways triggered by moreprolonged membrane depolarizations. However, Ca 1.2 and Ca 1.3 currents shown in Fig. 2 clearly activate with fast kinetics (Xu and Lipscombe 2001) and, although contrary tothe pervading viewpoint, these data are consistent with certainother studies. Cloned Ca 1.2 L-type channels have been shown to support at least as much calcium influx as Ca 2 channels, in response to brief action potential stimuli (Liu et al. 2003) andnative L-type channels mediate spike-induced calcium influx inhippocampal dendrites (Christie et al. 1995). It is likely thatactivation kinetics of L-type calcium channels will vary de-pending on several factors including cell-type, temperature,alternative splicing, and the presence of auxiliary subunits(Birnbaumer et al. 1998; Lipscombe 2002b; Liu et al. 2003).
For example, the Ca 1.2 clone isolated from rabbit heart used in our earlier studies (Xu and Lipscombe 2001) activates withkinetics that are slow as compared with our neuronal Ca 1.2 Ca 1.3 and Ca 1.2 L-type channels have different activation thresh- clone (Fig. 2). However, we also suggest that pharmacological olds. Whole cell currents measured from tsA201 cells expressing Ca 1.3 (A) subtraction methods used frequently to isolate L-type calcium and Ca 1.2 (B) together with Ca ␣ ␦ and Ca ␤ . Currents were activated by channels from other subtypes of voltage-gated calcium chan- step depolarizations to the indicated test potentials from a holding potential of ⫺100 mV; 2 mM Ca2⫹ was the charge carrier. C: averaged current–voltage nels in neurons, might have contributed to the notion that relationships for Ca 1.3 () and Ca 1.2 (E) channels. Activation V L-type calcium channels activate with slow kinetics (Fig. 3).
calculated from Boltzmann-linear fits were, ⫺40.4 ⫾ 0.9 mV and ⫺16.1 ⫾ 0.5mV for Ca 1.3 and Ca 1.2, respectively (n ⫽ 8, 11). For a more detailed description of methods see Xu and Lipscombe (2001). All clones were isolatedin our laboratory. Ca 1.3 and Ca ␣ ␦ clones were isolated from a rat sympathetic cDNA library, Ca 1.2 from mouse brain, and Ca ␤ from rat brain. Accession numbers are for Ca 1.3: AF370009; Ca 1.2: AY728090; Ca ␤ is identical to M88751; Ca ␣ ␦ : AF286488.
containing L-type calcium channels appear to be significantlyless sensitive to dihydropyridine antagonists (Koschak et al.
2001; Xu and Lipscombe 2001). This property complicatesidentification of Ca 1.3 currents. For example, ⬎90% of Ca 1.2 current is inhibited by 1 ␮M nimodipine, but this same concentration inhibits only 50% of peak Ca 1.3 current (Xu and Lipscombe 2001). Striessnig and colleagues obtained sim-ilar results using isradipine (Koschak et al. 2001). The lowersensitivity of Ca 1.3 channels to dihydropyridine antagonists becomes even more significant at hyperpolarized membranepotentials. Inhibition by dihydropyridines is state-dependent:enhanced at depolarized membrane potentials that open thechannel, but reduced at hyperpolarized membrane potentials(Bean 1984; Berjukow et al. 2000). Consequently, dihydro-pyridines become particularly ineffective at inhibiting Ca 1.3 currents activated at the foot of the current–voltage curve (Xu Dihydropyridine-sensitive component of the Ca 1.3 L-type current appears to activate slowly. A: representative Ca 1.3 currents in the absence and Lipscombe 2001). Interestingly, the Ca 1.3 current that (black) and presence (gray) of 1 ␮M nifedipine. Currents were activated by remains in the presence of dihydropyridines takes on the profile step depolarizations to the indicated potentials from a holding potential of of an inactivating current with barium as the charge carrier ⫺100 mV. Currents were recorded from Xenopus oocytes expressing Ca 1.3, (Fig. 3) (Xu and Lipscombe 2001). This is consistent with the Ca ␣ ␦, and Ca ␤ ; 5 mM barium is the charge carrier. Additional details can state-dependent nature of the block by dihydropyridines (Bean be found in Xu and Lipscombe (2001). B: subtracted Ca 1.3 currents showing the dihydropyridine-sensitive component at the indicated test potentials. Cur- 1984; Berjukow and Hering 2001). In their presence, Ca 1.3 rents appear to activate slowing because of the time-dependent nature of channels generate low-threshold, drug-resistant, inactivating dihydropyridine block. Scale bars: 0.5 ␮A, 20 ms.
J Neurophysiol • VOL 92 • NOVEMBER 2004 • www.jn.org L-TYPE CALCIUM CHANNELS The L-type calcium current in neurons is defined frequently as Avery and Johnston commented that ". . the designation ‘low- the whole cell calcium current that is inhibited by dihydropyr- voltage-activated' should not be limited to T-type channels." idine antagonists. Pharmacological subtraction is only appro- These investigators ". . challenge the traditional designation priate, however, when inhibition is complete, and independent of L-type channels as exclusively HVA and reveal a possible of voltage and time; conditions not met for dihydropyridine role in subthreshold Ca2⫹ signaling" (Avery and Johnston 1996).
block of Ca 1.3 L-type currents (Figs. 2, 3). Figure 3 illustrates Single-channel recordings also indicate differences among that Ca 1.3 L-type currents open with rapid kinetics, and neuronal L-type calcium channels in hippocampal pyramidal inactivate little with barium as the charge carrier. However, in and cerebellar granule cells (Forti and Pietrobon 1993; Kava- the presence of nimodipine, inhibition is incomplete and the lali and Plummer 1996; Schjott and Plummer 2000). Record- remaining current appears to inactivate. These data are consis- ings distinguish at least 2 gating activities of L-type calcium tent with the state-dependent nature of nimodipine block.
channels that may represent different channel subtypes. It will Consequently, the dihydropyridine-sensitive, subtracted cur- be interesting to determine their molecular origins.
rent appears as slowly activating, not because L-type calciumchannels open slowly but because the block is time-dependent and incomplete (Fig. 3).
Neuronal L-type calcium channels play established roles in Ca 1.4 L-type channels are functionally unique regulating gene expression, cell survival, and synaptic plastic- ity (Christie et al. 1997; Deisseroth et al. 1998; Galli et al.
Ca 1.4 was recently cloned from human and mouse retinal 1995; Mao et al. 1999; Marshall et al. 2003; Murphy et al.
tissue and heterologously expressed in mammalian cells (Bau- 1991; Norris et al. 1998; Weisskopf et al. 1999). In select cells mann et al. 2004; Koschak et al. 2003; McRory et al. 2004).
and synapses, L-type calcium channels can also regulate exo- Although currents generated from cells expressing Ca 1.4 cytosis (Ashcroft et al. 1994; Fuchs 1996; Heidelberger and clones were small, they had properties similar in several Matthews 1992; Liu et al. 2004; Sand et al. 2001; Thaler et al.
respects to those of Ca 1.3. These include rapid activation 2001; Wiser et al. 1999). In addition, data reviewed here kinetics, low activation threshold, and lower sensitivity to suggest Ca 1.3 L-type calcium channels mediate subthreshold dihydropyridine inhibition (Baumann et al. 2004; Koschak et calcium signaling. For example, dihydropyridine antagonists al. 2003; McRory et al. 2004). Native L-type currents in retinal suppress spontaneous intracellular calcium oscillations and cells, presumed to be Ca 1.4-containing (Taylor and Morgans slow rhythmic firing in several excitable cells, including cere- 1998; Wilkinson and Barnes 1996), are likewise similar to bellar Purkinje neurons, suprachiasmatic nucleus neurons, in- recombinant Ca 1.3 and Ca 1.4 channels. They have lower ferior olivary neurons, corticostriatial neurons, pituitary cells, sensitivity to dihydropyridines and activate at negative thresh- and GH3 cells (Charles et al. 1999; Giraldez et al. 2002; olds. These data are consistent with the relatively high level of Liljelund et al. 2000; Pennartz et al. 2002; Placantonakis and sequence homology between Ca 1.3 and Ca 1.4 genes (Fig. 1) Welsh 2001; Vergara et al. 2003). These studies and those that (Lipscombe 2002b). Heterologously expressed Ca 1.4 L-type show sinoatrial node dysfunction in Ca 1.3 knockout mice calcium channels are also distinctive in lacking calcium-de- (Mangoni et al. 2003; Platzer et al. 2000; Zhang et al. 2002) pendent inactivation (Baumann et al. 2004; Koschak et al.
strongly implicate Ca 1.3 L-type calcium channels in driving 2003; McRory et al. 2004). The currents in these studies were oscillatory activity. Ca 1.3 channels could also mediate sus- all relatively small but calcium entering through a single tained calcium entry during action potential plateaus, as calci- channel should be sufficient to support inactivation, if compo- um-dependent and voltage-dependent inactivation is minimal nents of the calcium-dependent inactivation pathway are at depolarized voltages (Figs. 2 and 3).
present (Peterson et al. 2000; Yue et al. 1990). The absence of Many neurons express low- to mid-threshold activating, calcium-dependent inactivation suggests that Ca 1.4 channels inactivating, and drug-resistant calcium currents collectively are functionally distinct from Ca 1.3 and Ca 1.2 channels called R-type. These currents are generally attributed to Ca 2.3 (Koschak et al. 2003; McRory et al. 2004).
channels (Cloues and Sather 2003; Magistretti et al. 2000;Randall and Tsien 1995; Tottene et al. 1996; Yasuda et al.
Native neuronal L-type currents are functionally diverse 2003). The properties of Ca 1.3 channels suggest that distin- guishing them from Ca 2.3 channels using dihydropyridine Certain cell-types, including hair cells, amacrine cells, and antagonists would be difficult. It is quite likely that Ca 1.3 endocrine cells express a limited number of calcium channels.
L-type calcium channels contribute a significant fraction of the Within this background, low-threshold dihydropyridine-sensi- R-type current in many neurons. The prevalence of significant tive L-type calcium currents are more readily identified (Ash- drug-resistant R-type currents in neurons of Ca 2.3 knockout croft et al. 1994; Habermann et al. 2003; Liu et al. 2004; mice strongly supports this proposal (Wilson et al. 2000).
Michna et al. 2003; Platzer et al. 2000; Schnee and Ricci 2003; R-type currents contribute to presynaptic transmitter release at Smith et al. 1993). Several groups also report low-threshold- certain synapses (Wu et al. 1999) and to synaptic plasticity in activating dihydropyridine-sensitive L-type currents in hip- dendritic spines of hippocampal pyramidal neurons (Yasuda et pocampal pyramidal, cortical striatal, suprachiasmatic, tha- lamic, and motor neurons with properties similar to Ca 1.3 Ca 1.3 L-type channels will activate in response to physi- channels (Avery and Johnston 1996; Cloues and Sather 2003; ological stimuli that do not open Ca 1.2 L-type channels. This Li and Bennett 2003; Liljelund et al. 2000; Pennartz et al.
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La lógica de la sobredeterminación: hacia una radica- lización del análisis político Resumen. El presente artículo se plantea, desde una gramática posfundacionalista, radicalizar el análisis político proponiendo a la sobredeterminación, en tanto lógica subyacente a todo proceso de significación, como un concepto clave para poder disolver las fronteras que le ha impuesto la ciencia política canónica. Procurando avanzar en una conceptualización de la noción de sobredeterminación, este trabajo intenta mostrar la presencia de la lógica de la sobredeterminación en una serie de investigaciones empíricas realizadas desde un marco analítico posfundacionalista, en cada una de las cuales se ausenta una discusión teórica en torno a esta noción clave.

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The Oncologist CME Program is located online at http://cme.theoncologist.com/. Symptom Management and Supportive Care The Assessment and Management of Delirium in Cancer Patients HIRLEY H. BUSH,a,b,c,d EDUARDO BRUERA aDepartment of Palliative Care & Rehabilitation Medicine, University of Texas M.D. Anderson Cancer