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Low-Threshold L-type Calcium Channels in Rat Dopamine Neurons

¹Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163; and ²Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta, Georgia 30310

Submitted 21 October 2003; accepted in final form 18 November 2003

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Ca²⁺ channel subtypes expressed by dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) were studied using whole cell patch-clamp recordings and blockers selective for different channel types (L, N, and P/Q). Nimodipine (Nim, 2 µM), -conotoxin GVIA (Ctx, 1 µM), or -agatoxin IVA (Atx, 50 nM) blocked 27, 36, and 37% of peak whole cell Ca²⁺ channel current, respectively, indicating the presence of L-, N-, and P-type channels. Nim blocked approximately twice as much Ca²⁺ channel current near activation threshold compared with Ctx or Atx, suggesting that small depolarizations preferentially opened L-type versus N- or P-type Ca²⁺ channels. N- and L-channels in DA neurons opened over a significantly more negative voltage range than those in rat dorsal root ganglion cells, recorded from using identical conditions. These data provide an explanation as to why Ca²⁺-dependent spontaneous oscillatory potentials and rhythmic firing in DA neurons are blocked by L-channel but not N-channel antagonists and suggest that pharmacologically similar Ca²⁺ channels may exhibit different thresholds for activation in different types of neurons.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Numerous studies have indicated that Ca²⁺ entry is important in regulating the firing patterns of dopaminergic (DA) neurons in the substantia nigra. The pacemaker-like slow depolarizations (PLSD), spontaneous oscillatory potentials (SOPs), and slow afterhyperpolarizations involved in regulation of DA neuron firing activity have all been shown to be Ca²⁺ dependent (Fujimura and Matsuda 1989; Grace and Onn 1989; Harris et al. 1989; Kang and Kitai 1993a,b; Mercuri et al. 1994; Nedergaard et al. 1993; Ping and Shepard 1996; Yung et al. 1991). A previous study suggests that DA neurons express L-, N-, P/Q-, and R-type Ca²⁺ channels (Cardozo and Bean 1995). However, the Ca²⁺ channel subtype(s) involved in regulation of DA neuron firing behavior have not been conclusively determined. In two studies, DA neuron spontaneous firing and SOPs were abolished by dihydropyridines but not -conotoxin GVIA (Ctx), suggesting a prominent role for L-, but not N-type Ca²⁺ channels in these phenomena (Mercuri et al. 1994; Nedergaard et al. 1993). However, Kang and Kitai (1993b) provided evidence that DA neuron pacemaker activity was underlain by N- but not L-type Ca²⁺ channels. Finally, a study by Fujimura and Matsuda (1989) suggested that neither N- nor L-channels were involved in DA neuron pacemaker activity.

The present study investigated the relative contribution of L-, N-, and P-type Ca²⁺ channels to whole cell Ca²⁺ channel current at different membrane potentials, to see which of the three channels opened at membrane potentials that would be commensurate with a role in the PLSD. We also compared the voltage dependence of DA neuron Ca²⁺ channel activation to that of dorsal root ganglion (DRG) neurons. Our data indicate that a larger proportion of the whole cell Ca²⁺ current observed near activation threshold is conducted through L-channels versus N- or P-channels, and that Ctx- and nimodipine (Nim)-sensitive Ca²⁺ channel currents activate over a more negative voltage range in DA neurons compared with DRG neurons. These data suggest that pharmacologically similar Ca²⁺ channels may exhibit different thresholds for activation in different types of neurons and support the previous studies suggesting that SOPs and rhythmic firing in DA neurons are blocked by L-channel but not N-channel antagonists.

	METHODS

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Isolation of neurons

Brain slices containing the substantia nigra pars compacta (SNc) were prepared from young Sprague-Dawley rats (Harlan) 13-17 days of age as described previously (Scroggs et al. 2001). For isolation of DA neurons, pieces of SNc were cut from the brain slices and incubated for 30 min at 35°C in Tyrode's (continuously bubbled with 100% O₂) containing 2 mg/ml pronase E (Sigma). After incubation the pieces of SNc were washed with Tyrode's solution containing (in mM): 140 NaCl, 4 KCl, 2 MgCl₂, 2 CaCl₂, 10 glucose, and 10 HEPES, pH 7.4 with NaOH. The pieces of SNc were then triturated in Tyrode's solution with a fine-bore Pasteur pipette and the resulting suspension was plated onto the bottom of a 35-mm plastic petri dish (Falcon) that served as a recording chamber. DRG cells were isolated from male Sprague-Dawley rats (50-100 g), as previously described (d'Alcantara et al. 2002). All procedures involving animals were approved by The University of Tennessee Health Science Center Animal Care and Use Committee.

DA neuron identification

An analysis of acutely isolated neurons from the SNc (Fig. 1A) using antibodies against tyrosine hydroxylase (TH) showed that 76% of the neurons that were 30 µm along one axis were TH positive (TH⁺), while only 18% of cells < 30 µm were TH⁺. Thus neurons 30 µm were chosen for recording. In addition, we characterized neurons regarding their expression of I_H and I_A, which are selectively expressed in DA neurons versus other neurons in the SNc (Grace and Onn 1989; Kang and Kitai 1993a,b; Yung et al. 1991). I_H was tested for with a family of voltage commands from a holding potential of -50 to -110 through -140 mV (Fig. 1B). I_A was tested for by a depolarizing voltage command to -10 from a holding potential of -70 mV (Fig. 1C). Only neurons that exhibited I_H and I_A were included in the study.

View larger version (35K): [in this window] [in a new window]   FIG. 1. Identification of acutely isolated SNc-DA neurons. A: digital image of a tyrosine hydroxylase positive (TH+) neuron adhered to the bottom of a 33-mm petri dish. The isolated neurons were plated onto a poly-L-lysine-coated coverslip and tested for expression of tyrosine hydroxylase (TH) using primary antibodies followed by diaminobenzene-conjugated secondary antibodies. The dark staining of the neuron in the center of the photograph indicates a positive reaction for TH. B: family of H-currents evoked in a putative acutely isolated SNc-DA neuron. C: blockade of IA by 4-aminopyridine in a putative SNc-DA neuron. The current was inward because there was no K+ added to the pipette solution and there was 4 mM K+ in the external Tyrode's solution.

All experiments were done at room temperature (23°C). Currents and voltages were recorded in the whole cell patch configuration using an Axopatch 200A, a Digidata 1200, and P-clamp 8.2 (Axon Instruments). Leak subtraction was carried out using the P/4 technique. Electrodes were coated with Sylgard to about 200 µm from the tip and fire polished to a final resistance of 2-4 M. Whole cell capacitance was not nulled so that series resistance could be estimated from capacity transients after compensation, as described previously (Scroggs and Fox 1992).

Solutions

Solutions superfusing the neuron under study were changed using a series of glass capillary tubes mounted on a motorized micromanipulator as described previously (d'Alcantara et al. 2002). The patch electrodes were filled with a solution containing (in mM): 190 N-methylglucamine, 5 2Na-ATP, 0.48 2Li-GTP, 0.1 mM BAPTA, and 40 HEPES, adjusted to pH 7.4 with H₂SO₄. I_A, and I_H were tested for in external Tyrode's solution containing 500 µM Cd²⁺ and 400 nM tetrodotoxin (citrate salt, Sigma). Ca²⁺ channel currents were isolated with a solution containing (in mM): 160 tetraethylammonium chloride, 2 BaCl₂, and 10 mM HEPES, pH 7.4 with tetraethylammonium hydroxide.

Data analysis

The effect of Ca²⁺ channel blockers Ctx, -agatoxin IV (Bachem), and nimodipine, (Sigma-Aldrich) on the whole cell Ca²⁺ channel current amplitude was estimated from plots of current versus time. Ca²⁺ channel current rundown was taken into account as described previously (Scroggs and Fox 1992). Best fit values for V_1/2 and the slope factor k for conductance-voltage relationships for activation were estimated by fitting the Boltzmann relationship: g = g_max/{1 + exp[(V_1/2 - V_M)/k]}, to the conductance observed at different test potentials. The data are presented as the mean ± SE.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
The effects of 2 µM Nim, 1 µM -agatoxin GVIA (Atx), and 50 nM Ctx on peak Ca²⁺ channel current amplitude was assessed in 33 putative DA neurons identified as described under METHODS (see Fig. 1). The blockers were studied in pairs (Nim vs. Ctx, n = 10; Nim vs. Atx, n = 11; Ctx vs. Atx, n = 12), and their order of addition was varied to address specificity. On average Nim (n = 21), Atx (n = 23), and Ctx (n = 22) blocked 27 ± 1.9, 34 ± 1.3, and 36 ± 1.2% of whole cell current, respectively (Fig. 2). The average effects of the blockers were changed by 5% or less when added before versus after another blocker (not significant). Addition of all three blockers simultaneously reduced whole cell Ca²⁺ channel current by an average of 85 ± 1.2% (n = 5).

View larger version (32K): [in this window] [in a new window]   FIG. 2. Effects of nimodipine (Nim) -agatoxin IVA (Atx), and -conotoxin GVIA (Ctx) on whole cell Ca2+ channel current amplitude in acutely isolated DA neurons. A, C, and E: plots of Ca2+ channel current versus time, showing the reduction of current amplitude produced by application of 2 µM Nim, 50 nM Atx, or 1 µM Ctx (A, C, and E, respectively) and then a further reduction produced by subsequent addition of 1 µM Ctx, 2 µM Nim, or 50 nM Atx (A, C, and E, respectively) in the continued presence of the first blocker. B, D, and F: plots of current-voltage (I-V) relationships for activation of Ca2+ channel current in the experiments depicted in A, C, and E, under initial control conditions, after treatment with the first and second blockers. Each data point represents the average of several identical experiments (A, n = 4; C, n = 6; and E, n = 8). The amplitudes of the data points have been corrected for rundown based on the estimated percent reduction of peak current produced by the various blockers in each case.

View larger version (27K): [in this window] [in a new window]   FIG. 3. Comparison of percent blockade and g-V relationships versus test potential for Atx-, Ctx-, and Nim-sensitive current. A: plot of the percentage of total whole cell current blocked by Atx, Ctx, and Nim at test potentials ranging from -50 to 0 mV. B: plots of g-V relationships for Atx-, Ctx-, and Nim-sensitive current in acutely isolated DA neurons (closed symbols, solid lines) and for Ctx- and Nim-sensitive current in small diameter dorsal root ganglion cells (open symbols, dashed lines). The current sensitive to the different toxins was quantified by measurement of I-V curves fitted with splines in Systat (SPSS) at points corresponding to -50 through 0 mV in 5-mV increments. The lines were fitted to the control and treatment data points using a Boltzmann function as described under METHODS. The error bars represent the SE.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
The major finding of this study is that, in DA neurons, current conducted through L-type Ca²⁺ channels makes up the bulk of whole cell Ca²⁺ channel current evoked by small depolarizations near the activation threshold. These data support previous studies showing that SOPs and spontaneous firing are abolished by L-channel blockers (Mercuri et al. 1994; Nedergaard et al. 1993). SOPs and the PLSD, which underlie regular spontaneous firing, generally involve fluctuations of the membrane potential between around -50 and -40 mV, where L-channel current may comprise the bulk of the whole cell Ca²⁺ current in DA neurons. Conversely, N-channel current appears to account for a much smaller fraction of whole cell Ca²⁺ current over this same voltage range, which could explain why the N-channel antagonist Ctx did not abolish SOPs or spontaneous firing in DA neurons in two studies (Fujimura and Matsuda 1989; Nedergaard et al. 1993).

Our estimates of current block by Nim, Ctx, and Atx are probably not highly accurate representations of the contribution of L-, P-, and N-channels to whole cell Ca²⁺ channel current at different membrane potentials under physiological conditions. The permeability of the different channels to Ba²⁺ is different from that for Ca²⁺. Also, the presence of rundown likely generates error in the quantification of the block. Finally, 2 mM Ba²⁺ externally and the N-methyl-D-glucamine-based internal solution both produce negative shifts in the voltage-dependency of Ca²⁺ channels (Bargas et al. 1994; Hille 1992; Malecot et al. 1988). Although, regarding this last point, a previous study using Ca²⁺ imaging suggests that the threshold for Ca²⁺ entry in DA neurons is around -50 mV (Wilson and Callaway 2000), similar to what we observed for Ba²⁺ in this study.

Despite the above caveats, our finding that L-channel current predominates over N- and P-current during small depolarizations is likely qualitatively accurate. Nim, Ctx, and Atx each appeared to have a robust effect, and there was little overlap in the fractions estimated targeted by each agent, which should have been detected by changing the order of addition. The lack of overlap is not surprising since Nim, Ctx, and Atx have been shown to be selective for L-, N-, and P/Q-channels, respectively, at the concentrations we used (Boland et al. 1994; Mintz et al. 1992; Randall and Tsien 1995; Sather et al. 1993). Thus relatively pure and robust Nim-, Ctx-, and Atx-sensitive current fractions could be identified by subtraction and compared regarding their respective g-V relationships.

The relative nature of the g-V relationships for Nim-, Ctx-, and Atx-sensitive current would not likely be affected by a lack of saturation by one or more blockers, unless DA neurons express subpopulations of channels that have a differential sensitivity to a given blocker. For example, we did not prove that 2 µM Nim is a saturating concentration regarding L-channels in DA neurons, and different types of L-channels may vary in their sensitivity to Nim. Thus higher concentrations of Nim could block a second population of L-channels that have a g-V relationship closer to that of N- or P-channels. However, this possibility does not preclude the observation that 45-50% of the current evoked by test potentials ranging from -50 to -35 mV was blocked by 2 µM Nim. Another issue is the possibility that the 50 nM concentration of Atx used could have blocked a small fraction of Q-channels in addition to P-channels. However, in a previous study (Cardozo and Bean 1995), 200 nM Atx was observed to block a similar percentage of current (35%) in DA neurons as was blocked by 50 nM Atx in our study. This suggests that contamination of the Atx-sensitive fraction with Q-channels was minimal in our study. In any case, the current resistant to the three blockers added simultaneously activated over a voltage range similar to the Ctx- and Atx-sensitive fractions, indicating that unblocked Q-current and R-current also activated over a more positive voltage range than that blocked by 2 µM Nim.

The available data suggest that L-channel activation over significantly more negative membrane potentials compared with N or P/Q channels occurs in some neurons but not others. We observed a similar 5 mV difference in the V_1/2 for Nim- and Ctx-sensitive current in small diameter DRG cells. In addition, this phenomenon has been observed in striatal medium spiny neurons, chick sensory neurons, and NG108 -15 cells (Aosaki and Kasai 1989; Bargas et al. 1994; Kasai and Neher 1992), but does not appear to occur in neocortex pyramidal neurons (Lorenzon and Foehring 1995). Possibly subtypes of pharmacologically similar channels may account in part for these variations. For example, some previous studies have suggested that _1D-class L-channels have a lower threshold for activation than _1C-class L-channels (Fisher and Bourque 1996).

The acutely isolated DA neurons in this study included only the soma and short dendritic stumps. However, a previous study using Ca²⁺ imaging found that 5 µM nifedipine (an L-channel antagonist) abolished Ca²⁺ oscillations and decreased Ca²⁺ concentration by 50% in both the dendrites and the soma of SNc-DA neurons recorded from brain slices (Kalume and Callaway 1999). Thus L-channels may mediate the bulk of Ca²⁺ entry near activation threshold in DA neuron dendrites as well as somata.

In addition to providing a likely explanation for why selective L-channel blockers abolish SOPS and spontaneous firing in DA neurons, our study suggests that pharmacologically similar Ca²⁺ channels may activate over significantly different voltage ranges in different types of neurons. In the present study N- and L-type Ca²⁺ channel current activated over a significantly more negative voltage range in DA neurons versus DRG neurons. A similar difference in voltage of activation of whole cell Ca²⁺ channel current (recorded using the same solutions) is apparent regarding striatal medium spiny neurons and neocortical neurons, which are similar to each other regarding the magnitude of L-, N-, P/Q-, and R-current fractions (Bargas et al. 1994; Lorenzon and Foehring 1995).

In summary, we conclude that L-channels play a critical role in the firing behavior of DA neurons. In DA neurons, current conducted through L-channels predominates over that conducted through other types of Ca²⁺ channels at voltages ranging from around -50 to -40 mV, where Ca²⁺ entry helps drive DA neurons to action potential threshold.

	ACKNOWLEDGMENTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Present address of P. Durante: Faculty of Life Sciences, Division of Molecular Physiology, University of Dundee, DDI 5EH Scotland, UK.

GRANTS

This research was supported by National Institute of Neurological Disorders and Stroke Grants NS-39163, NS-37067, and by U54-36194.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Address for reprint requests: R. Scroggs, University of Tennessee Health Science Center, Department of Anatomy and Neurobiology, 855 Monroe Ave., Memphis, TN 38163 (E-mail: rscroggs{at}nb.utmem.edu).

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This Article Abstract Full Text (PDF) All Versions of this Article: 91/3/1450    most recent 01015.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Durante, P. Articles by Scroggs, R. S. Search for Related Content PubMed PubMed Citation Articles by Durante, P. Articles by Scroggs, R. S.