Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by Divalent Cations and Polyamines

Eric M. Lasater; Eduardo Solessio

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Regulation of Voltage-Sensitive Ca²⁺ Channels in Bipolar Cells by Divalent Cations and Polyamines

Eric M. Lasater and Eduardo Solessio.

Ca²⁺plays a key role in intracellular signal transduction in neurons but in excess it can lead to cell death. Thus its entry into cells is highly regulated by both extrinsic and intrinsic mechanisms. Little is known of the regulation of Ca²⁺ entry into retinal neurons. Here we describe the role of divalent cations and polyamines as intrinsic modulators of Ca²⁺ entry into retinal bipolar cells. Cone-dominant (small) bipolar cells of the white bass retina were studied using whole cell patch clamp techniques. With biophysical and pharmacological tools it was determined that these cells expressed a Ca²⁺ current similar to an L-type current. This current was very susceptible to blockage by divalent cations including Ca²⁺. In addition, when tested with the polyamines, spermine, spermidine and putrescine, only spermine effectively inhibited the current. When the dose-response curve was fit with the Hill function we found an EC₅₀ of 28 mM and a Hill coefficient of about 2. Our results indicate that divalent cations and the polyamine, spermine, are effective modulators of calcium entry into cone-dominated bipolar cells. The in vivo regulation of the concentrations of these molecules provides an exquisitely sensitive mechanism for regulating Ca²⁺ entry into bipolar cells under different conditions.

Introduction

Transient changes in cytosolic Ca²⁺ play a pivotal role in intracellular signaling in neurons. Ca²⁺ modulates pathways such as dendritic signal integration, neurotransmitter release, synaptic plasticity, and ligand-gated ion channel function. The primary mechanism for increasing intracellular Ca²⁺ levels is by Ca²⁺ entry through voltage-activated Ca²⁺ channels.¹ Neuronal Ca²⁺ channel activity is regulated as a means of controlling the amount of Ca²⁺ entering the cell. For example, neurotransmitters and neuromodulators as well as intrinsic agents such as divalent cations and polyamines have been shown to modulate the flow of Ca²⁺ through various types of Ca²⁺ channels.^2,3 At present, our understanding is incomplete of the mechanism(s) of Ca²⁺ entry into retinal neurons and, in particular, the regulation of this entry.

In the retina, bipolar cells are second-order neurons that transfer information from the distal to the proximal retina. In the distal retina, they make synaptic contact with photoreceptor cells and horizontal cells and in the inner retina they are in contact with amacrine cells and ganglion cells.⁴ In some species they are also in contact with interplexiform cells.⁵ As with all neurons, Ca²⁺ entry into bipolar cells plays an important role in intracellular signal transduction processes including neurotransmitter release. This entry is regulated by a number of processes including the actions of neurotransmitters and neuromodulators. As mentioned above, in other neuronal systems, mechanisms intrinsic to the cell also have been shown to modulate Ca²⁺ channel activity⁶ but little is known about this in retinal bipolar cells. In fact, such intrinsic mechanisms have not been studied in detail in retinal neurons other than in photoreceptor cells.

In an effort to better understand intrinsic mechanisms that might regulate Ca²⁺ entry into bipolar cells, we studied Ca²⁺ currents found in isolated teleost bipolar cells. Here we report on divalent cations and the polyamine spermine as a mechanism for the bipolar cell to regulate its Ca²⁺ current and thus, the amount of Ca²⁺ entry into these cells.

Methods

Preparation

This study was conducted on bipolar cells isolated from the retina of the white bass (Morone chrysops). We have described the isolation procedure in detail in the past.⁷ In brief, eyes were removed from the fish following euthanasia in accordance with the guidelines set out by the Association for Research in Vision and Ophthalmology for the Use of Animal in Research. Retinas were removed from the eyes and placed in an enzyme (papain) solution. Following incubation, the retinas were then triturated and plated out into cell culture dishes. The cells were then used after between one to seven days in culture. Two types of bipolar cells result from the trituration procedure. Bipolar cells were identified by their characteristic morphology⁷ (see below).

Solutions

At the beginning of each experiment the tissue culture medium in a dish was replaced with white bass Ringer's containing the following (in mM): 130 NaCl, 2.5 CaCl₂, 2.8 KCl,1 MgCl₂,10 glucose and 8.4 HEPES. The pH was adjusted to 7.4 using NaOH. The recording pipette solution contained (in mM): 120 cesium chloride, 4 NaCl, 11 EGTA, 1 MgCl₂, 8.4 HEPES and 20 tetraethylammonium. For the divalent free solution, both magnesium chloride (MgCl₂) and calcium chloride (CaCl₂) were omitted and EDTA and EGTA were added at 5 mM each. In the Na free solution, NaCl was replaced with an equimolar amount of choline chloride.

Solutions were applied from a microperfusion system (DAD12, ALA Scientific Instruments, Westbury, NY). Drugs could be rapidly applied and the solutions completely bathed the cell under study. Unless otherwise indicated, cells were perfused with the divalent free solution prior to test agent application. The test agents were dissolved in the divalent-free media.

Recording Procedures

Whole cell recordings were made with micropipettes that had been pulled on a two-stage puller (Narishige Instruments, Tokyo, Japan) and were used unpolished. The electrode tip resistance when measured in the bath solution was from 5 to 7 MΩ. Electrode capacitance and series resistance were compensated for electronically. Electrical potentials were recorded using an Axopatch 200A amplifier (Axon Instruments, Union City, California). A personal computer interfaced to a Digidata 1200 data acquisition system driven by the pClamp suite of programs (Axon Instruments) controlled data collection and analysis. The recordings shown are representative of three or more samples.

Results

In isolation, bipolar cells were identified by their characteristic shape. There are two types of bipolar cells found in the white bass retina following isolation.⁷ One has been termed a large bipolar and the other a small bipolar. The large bipolar corresponds to the mixed rod cone bipolar found in the teleost retina⁸ which is characterized by a relatively large cell body with several apical processes opposite of which is a long thin axon that ends in a relatively large oval terminal. Small bipolar cells have a small oval or tear-shaped soma and on the apical end, contain several small, fine dendritic processes. A long thin axon emanates from opposite the apical end to terminate in a small axonal terminal. These likely correspond to cone-dominated teleost bipolar cells. Our studies here were confined to the small bipolar cell type.

The complete membrane properties of bipolar cells in the bass retina have been previously described⁷ so we won't go into the details here. In Figure 1, in the upper left corner, is illustrated a control voltage clamp recording from a small bipolar cell. The current response to voltage commands is characterized by a slowly activating inward current that is characteristic of an inwardly rectifying H-type K current.⁹ Depolarizing responses are characterized by a slowly activating outward K current (IK_V). Also present in these cells, but not visible in the control recordings because ofthe large K currents, is a small inward Ca²⁺ current which is elicited at voltage levels more positive than the holding potential.⁷

Figure 1

Typical voltage clamp responses of a cone-dominated bipolar cell. Upper left. The cell was held at 70 mV and stepped in 20-mV increments above and below the holding potential, ranging from 120 mV to +80 mV. The response is characterized by a slowly activating (more...)

Since it was our desire to study the Ca²⁺ current, we tried to bring out the current by taking advantage of the fact that in a zero divalent cation solution, Ca²⁺ channels are highly permeable to monovalent ions and will conduct Na ions readily, generating a measurable inward current.¹⁰ It also took Ca²⁺ and Mg²⁺ away as possible modulators of the channel allowing us to study their action in isolation. So, voltage clamp recordings in a divalent free extracellular solution were made and revealed small voltage-dependent changes in the bipolar cell currents. This is illustrated in the upper right panel of Figure 1. In the lower half of the figure are shown current-voltage relationships measured 5 milliseconds after the onset of the voltage command (left) and 50 milliseconds following the onset of the voltage command (right). What was seen was a change in the outward currents evoked by the voltage steps. They increased in magnitude over control values at more depolarized levels. However, no inward current appeared in the voltage range typical of Ca²⁺ currents. It seemed likely that this was due to masking by K currents which were still relatively large.

We next blocked the inward and outward K currents with 20 mM TEA in addition to cesium replacing K ions in the intracellular recording solution. This revealed a reduction in the K currents observed. The effect is illustrated in Figure 2. In the upper left corner is shown a control recording; the Ca²⁺ current was still not very prominent. We went on and tried the intracellular TEA in the presence of zero divalent Ringer's. The result of this manipulation is shown the upper right corner of the figure. In the zero divalent solution, both the inward and outward currents have increased in magnitude. The difference between the control currents (TEA and cesium in the pipette) and the zero Ca²⁺, zero Mg²⁺/control currents revealed the true inward current. In the lower right corner of Figure 2 is a current-voltage relationship illustrating the three recording conditions. One can see that the inward current was activated at around 50 mVs and reached a peak at about 20 mVs. Hence forth, all future recordings were made with TEA in addition to cesium in the recording pipette. Also, the I-V curves illustrate that the magnitude of the current was relatively small. We found this to be the case in all small bipolar cells from which we recorded.

Figure 2

Typical voltage clamp recordings from a small bipolar cell with 10 mM TEA in the intracellular pipette solution. Upper left is the control recording. The cell was held at 70 mV and stepped from 80 mV to +60 mV in 10-mV increments. Only every other trace (more...)

The I-V relationship and sustained time course of the currents that we recorded were similar to that of a high voltage-activated, L-type Ca²⁺ current, although the peak current occurred at a more hyperpolarized level than is characteristic for most L-type currents. However, we recorded this current in a zero Ca²⁺ medium. Thus, this current may be carried by Na ions flowing through Ca²⁺ channels.¹⁰ We next determined that in fact, it was the case that Na was flowing into these cells through voltage-activated Ca²⁺ channels and we further characterized the channel. Figure 3 (left) illustrates the effects of the Na channel blocker TTX on the current. Recordings were done in control conditions, zero Ca²⁺/Mg²⁺ solution and in the presence of TTX (10 mM). The I-V relationship shows the current in zero Ca²⁺/Mg²⁺ solution (open triangles) and the results of the application of TTX (solid squares). The TTX had no effect on the current measured, indicating that the current was not flowing through voltage-dependent Na channels. We then subjected the cells to a solution containing zero Na (see methods). Under these conditions, no current was observed to flow into the cell over the activation range for the Ca²⁺ channels (open diamonds). In a second set of experiments, we found that the Ca²⁺ channel blocker, nifedipine (10 μM), substantially inhibited the current. This is shown in Figure 3 to the right. The application of nifedipine resulted in an I-V curve in which the current was reduced by about 80% (solid triangles). Washing the cell with zero Ca²⁺/Mg²⁺ media resulted in a return to control as illustrated by the curve plotted with the open triangles. The L-type Ca²⁺ channel blocker diltiazam had a similar effect (not shown). The results from Figure 3 illustrate that indeed we are observing Na ions flowing through the bipolar cell Ca²⁺ channels in a zero Ca²⁺/Mg²⁺ solution and that these channels are likely to be similar to L-type channels. Consequently, we are able to measure the bipolar cell Ca²⁺ current in an indirect fashion and examine the modulatory actions of Ca²⁺ and Mg²⁺ in isolation.

Figure 3

Effect of TTX and nifedipine on the inward current recorded from a small bipolar cell. Left figure shows the effects of TTX. Plotted with the closed circles is the control response and plotted with the open triangles is the response in the presence of (more...)

We next investigated the susceptibility of the current to block by divalent cations. Surprisingly, we found that as little as 0.1 mM Ca²⁺ in the extracellular media would substantially reduce the current. This is shown in Figure 4 (left). In this I-V plot, the current carried by Na through the Ca²⁺ channels is illustrated by the trace with the open circles. The trace with the solid triangles illustrates the current flowing through these channels when 0.1 mM Ca²⁺ is present in the bathing media. The current has been reduced by about 90% (the degree of block remained unchanged in 2.5 mM Ca²⁺). In a similar fashion, the divalent cation Ba²⁺ is also able to inhibit the current, but not to the same degree as Ca²⁺. This is illustrated in Figure 4, right, by the trace with the open triangles. Interestingly, increases in the concentration of Ba²⁺ did not improve the block. Rather, there was a depolarizing shift in the activation voltage and an increase in the peak current observed. Increasing the Ba²⁺ concentration from 0.1 mM to 1.0 mM produced a reduction in the size of the observed current. However, further increasing the concentration of Ba²⁺ to 10 mM caused a subsequent increase in the size of the current as well as a depolarizing shift in the activation range.

Figure 4

Block of the inward current by divalent cations. Left panel shows the I-V relationship for small bipolar cell responses in zero Ca²⁺/Mg²⁺ solution when being blocked by low Ca²⁺ (filled triangles) or Ba²⁺ (open triangles). Ca²⁺, 0.1 mM, substantially (more...)

The results of Figure 4 (right) can be explained in terms of an anomalous molefraction effect between Na and Ba²⁺ ions⁹ in a multiion pore: in a divalent free solution, Na ions flow freely through the pore. At low concentration, Ba²⁺ is entering the Ca²⁺ channel but likely binding, thus producing a small block of the Na currents. At higher concentrations the repulsion between Ba²⁺ ions drives the current across the channels, which is now carried by Ba²⁺ ions. Anomalous molar fraction effects have been described in L- and N-type Ca²⁺ channels^11,12 and in fact accounts for why Na can flow through the channel in the absence of divalents.¹³ The shift in the activation range has been previously observed and is probably related to surface charge effects.

Intracellular polyamines at endogenous concentrations have been shown in past studies to block or modulate K channels,^14–16 glutamate-activated channels¹⁷ and nicotinic acetylcholine activated ion channels¹⁸ in a voltage-dependent fashion. Polyamines applied extracellularly can also block K currents¹⁹ and L-type Ca²⁺ currents.²⁰ So, we next investigated the effects of polyamine application. Figure 5A shows the effect of the polyamine spermine in zero Ca²⁺/Mg²⁺ media. The closed circles represent the control Na current. Application of spermine reduced the current by about 80%. We went on and tested other polyamines. Extracellular application of 200 μM putrescine had no effect on the divalent free currents (not shown). The polyamine spermidine (200 μM) did not show a blocking action although it tended to broaden the I-V relationship somewhat.

Figure 5

Effects of polyamines on the inward current. The I-V relationship plotted with the open triangles is that which was obtained when the cell was superfused with 200 mM of the polyamine spermidine (SPD). Spermidine had little effect on the current flow into (more...)

We found the block by spermine to be concentration dependent. This is illustrated in Figure 5B. Here the control I-V relationship of the Na current flowing through Ca²⁺ channels is compared to the currents measured with the application of 15, 30 and 120 mM of spermine. As can be seen from the I-V traces, as the concentration of the applied spermine increased, the peak of the I-V curve systematically became smaller. This dose-response relationship is plotted in Figure 5C. The response curve was then fit with the Hill function. From this we obtained an EC₅₀ of 28 μM and a Hill-coefficient (n) of ˜2.0.

An unexpected effect was observed with the application of very high concentrations of spermine. This is illustrated in Figure 6. Rather than increasing the block of the current through the channel, a linear current developed. In the presence of a very low concentration of Ca²⁺ and Mg²⁺ (0.5 mM) the current through the Ca²⁺ channel carried by Na was blocked. In this same solution, with the application of 2 mM spermine, a large inward current was seen. When 2 mM of spermine was applied in the presence of a normal concentration of Ca²⁺ and Mg²⁺ (2.5 mM) the inward current was reduced by more than two-fold. The high concentration of spermine also eliminated the voltage-sensitive characteristics of the channel for unknown reasons. This may be due to surface charge effects or mass action simply driving the spermine through the channel. When the cells were returned to the control Ca²⁺/Mg²⁺ solution in the absence of spermine, the inward current was once again blocked. This indicates that the cell remains viable and this current was not due to some kind of toxic effect by the spermine. Results from this experiment suggest that at very high concentrations, spermine is able to flow through the Ca²⁺ channel without binding and producing a block. This is analogous to the block of rod photoreceptor cGMP-gated channels by spermine.²¹

Figure 6

Permeation of the bipolar cell Ca²⁺ channel by spermine. At high concentrations the spermine (SPM) is able to permeate the channel rather than produce a block (open triangles) in low divalent extracellular solution. The current produced by a high concentration (more...)

Conclusion

Intrinsic mechanisms play an important role in altering an ion channel's ability to conduct current and thus regulate ion entry into a cell. In this study we have shown that divalent cations and the polyamine spermine play a central role in the modulation of Ca²⁺ channel conductance in teleost, cone-dominated bipolar cells (small bipolars).

Bipolar Cell Ca²⁺ Channels

Previous studies have demonstrated several types of Ca²⁺ channels in retinal bipolar cells. In rodents, both low voltage activated (LVA) and high voltage activated (HVA) currents are present.^22,23 In lower vertebrates only HVA currents have been reported in bipolar cells of goldfish^24,25 salamander²⁶ and in ‘large’ (mixed rod-cone) bipolar cells of white bass,⁷ HVA and LVA Ca²⁺ currents are closely associated with neurotransmitter release in bipolar cell synaptic terminals.^24,27,28

Consistent with this, HVA Ca²⁺ channels locate at higher densities in the synaptic terminal.^24,25 Althought we did not record specifically from axon terminals, a presynaptic localization of Ca²⁺ channels is also likely in the case of the small bipolar cells in bass as can be inferred from our results in figures 1 and 2. As noted, the cells were clamped at the soma and not the synaptic terminal which here is very small in size (<3–4 μm). This is unlike the mixed rod-cone, Ab, bipolars in goldfish and carp that can have a terminal of ˜10 μm in diameter. In our studies, the currents through the Ca²⁺ channels were only evident (of sufficient magnitude) after blocking the K channels, suggesting that the channel blockage improved the capacity to adequately clamp the terminal at the end of the long and thin axonal process. While there is a high concentration of Ca²⁺ channels in the axon terminal, this is not to suggest that they solely contributed to the currents we recorded. It is likely that some of the Ca²⁺ channels underlying the Ca²⁺ currents, were located in other regions of the cell.

Despite the improved clamping conditions, we had to go to a divalent-free medium to enhance the magnitude of the currents flowing through the Ca²⁺ channels.¹⁰ Under these conditions the currents are carried by monovalent ions, predominantly Na. The currents are sustained in nature, and triggered at relatively depolarized levels. They are sensitive to nifedipine and not to TTX, consistent with the idea that although the currents are not carried by divalent ions, they flow through Ca²⁺ channels exhibiting anomalous mole fraction effects and increased permeability to Ba²⁺ ions. The I-V curve and the pharmacological sensitivity of the current suggest that it is flowing through channels that are, or closely resemble, L-type Ca²⁺ channels. This is consistent with results from other lower vertebrates.^24,25

It is intriguing however that under normal conditions the magnitude of the current is negligible and cannot readily be measured. One possibility is that the small size of the synaptic terminal in these particular cells, if this is where the channels are predominantly located, results in a scaled down magnitude of the current. A second possibility is that conditions in culture may alter expression of the channels, or it may be possible that these are ‘silent’ currents that a regulatory agent, may modulate in amplitude^25,29 and are only active under certain conditions. Lastly, they may simply be blocked in culture by the concentrations of divalents in the recording solution.

Ca²⁺ Channel Block

In cone-dominated bipolar cells, we found that the extracellular divalent cations Ca²⁺, Mg²⁺ and Ba²⁺ blocked the Ca²⁺ channels at physiological concentrations. In the absence of divalents, Na permeates the channel. This is due to the permeation properties of the channel. Energy profiles suggest that two Ca²⁺ ions are involved in the permeation process, whereas for Na, three ions are involved.¹³ Because of the energy profiles in the channel, it is easy for a Ca²⁺ ion to enter and drive out one or more Na ions, but once a Ca²⁺ ion is in the channel Na ions cannot do the same.¹³ A similar situation exists for Mg²⁺ and Ba²⁺, however, as illustrated by the “anomalous molefraction effect”, Ba²⁺ is less effective as a blocker.

We found that extracellular application of the polyamine spermine can reduce the magnitude of these currents at relatively low concentrations (EC₅₀ = 28 μM). Polyamines are a group of amine containing compounds that are synthesized as an intermediate as part of the catabolism of arginine.³⁰ Normally the intracellular concentration is highly regulated.³¹ Levels can rise under various conditions including in a circadian cycle³²and interact with cellular processes in a variety of ways.^3,31 As we showed here, in retinal bipolar cells they seem to interact with Ca²⁺ channels and alter the magnitude of the Ca²⁺ currents. Along these lines, in the case of certain disease states³³ and cell lysis, local extracellular levels of spermine could rise to micromolar levels blocking entry of Ca²⁺, and perhaps exert a neuroprotective effect.

The mechanism by which polyamines act as Ca²⁺ channel blockers is related to their binding within the pore. We found spermine to be the most effective polyamine blocker. Spermine has four positive charges whereas spermidine has three, ³ so spermidine may not bind as effectively. As mentioned, two Ca²⁺ ions seem to be involved in the permeation process,¹³ suggesting that there are two binding sites for Ca²⁺ within the channel. Spermine more effectively interacts with these binding sites to effect a block. In fact, we found a Hill coefficient of ˜2 for spermine block, suggesting that a spermine molecule is binding at each site. This mechanism appears to be the way by which the polyamine toxin FTX acts.^2,34,35 Or, it may be that spermidine binds, but because of its smaller size is not a sterically effective blocker.³⁶ It is interesting that at low concentrations spermine blocks the channel but at high concentrations permeates it. This suggests that the block is probably only weakly to moderately voltage dependent³⁶ although we did not test this specifically. Permeation of the channel also indicates that the block may not be difficult to overcome under certain circumstances.

Functional Implications

Our results here suggest that divalent cations and polyamines are effective agents for modulating Ca²⁺ entry into bipolar cells. In vivo, at rest it is likely little or no Ca²⁺ would enter the cell. Upon depolarization, only small amounts would enter, assuming normal levels of extracellular cations and physiological levels of polyamines.³¹ Should these levels be decreased, more Ca²⁺ would flow into the cell. In photoreceptors, it has been shown that polyamines block photoreceptor cyclic nucleotide-gated channels from both sides of the membrane.²¹ From the outside it acts as a permeant blocker. Lu and Ding ²¹ suggest that the polyamine blockmay play a role in suppressing noise in the signal transduction cascade in that it would prevent indiscriminant entry of Ca²⁺ which has a major role in the phototransduction cascade. Polyamines may be acting similarly in preventing Ca²⁺ entry into bipolar cells under particular conditions or at particular membrane potential levels. This then might prevent ‘noise’ in synaptic transmission under certain circumstances such as low light levels.

Obviously the concentration of extracellular cations and polyamines will determine the level of block that occurs. Along these lines, it is interesting that the concentrations of polyamines at which we observed a block, is roughly 30–300-fold lower than that which was needed for block in NMDA-activated channels.^2,37–39 This suggests that extracellular polyamine concentrations are highly regulated in the retina and may exist at lower levels than found in the CNS, otherwise these channels might be permanently blocked. Unfortunately we know little of how or under what circumstances retinal levels of divalents and polyamines might be regulated. In other systems a variety of mechanisms exist for up and downregulating cation levels (transport, intracellular release, sequestering, etc.)^1,40–42 and polyamine levels (ie. synthesis, transport, degradation, etc).^3,30,31 These mechanisms may be active in the retina or it may be possible that function is regulated by activity.¹⁷ In this instance, increased levels of activity could lead to a decrease of synaptic levels of divalents and polyamines, resulting in greater influx of Ca²⁺. It is possible that M¨ller cells provide such a mechanism for clearing divalents and polyamines from the synaptic cleft.^43–45 Whatever the case, it is clear that divalent cations and polyamines are powerful intrinsic modulators of bipolar cell Ca²⁺ channel activity.

Acknowledgments

This work was supported by an NIH grant EY05972 (E.M.L.) from the National Eye Institute and an unrestricted grant to the Department of Ophthalmology and Visual Sciences, University of Utah from Research to Prevent Blindness, Inc. (RPB). E.M.L. is an RPB Lew R. Wasserman Merit awardee.

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Lasater EM, Solessio E. Regulation of Voltage-Sensitive Ca2+ Channels in Bipolar Cells by Divalent Cations and Polyamines. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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