Correspondence to: Richard Payne, Department of Biology, University of Maryland, College Park, MD 20742. Fax:301-314-9358 E-mail:rp12{at}umail.umd.edu.
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Abstract |
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Light-induced release of Ca2+ from stores in Limulus ventral photoreceptors was studied using confocal fluorescence microscopy and the Ca2+ indicator dyes, Oregon green-5N and fluo-4. Fluorescence was collected from a spot within 4 µm of the microvillar membrane. A dual-flash protocol was used to reconstruct transient elevations of intracellular free calcium ion concentration (Cai) after flashes delivering between 10 and 5 x 105 effective photons. Peak Cai increased with flash intensity to 138 ± 76 µM after flashes delivering ~104 effective photons, while the latent period of the elevation of Cai fell from ~140 to 21 ms. The onset of the light-induced elevation of Cai was always highly correlated with that of the receptor potential. The time for Cai to exceed 2 µM was approximately equal to that for the receptor potential to exceed 8 mV (mean difference; 2.2 ± 6.4 ms). Cai was also measured during steps of light delivering ~105 effective photons/s to photoreceptors that had been bleached with hydroxylamine so as to reduce their quantum efficiency. Elevations of Cai were detected at the earliest times of the electrical response to the steps of light, when a significant receptor potential had yet to develop. Successive responses exhibited stochastic variation in their latency of up to 20 ms, but the elevation of Cai and the receptor potential still rose at approximately the same time, indicating a shared process generating the latent period. Light-induced elevations of Cai resulted from Ca2+ release from intracellular stores, being abolished by cyclopiazonic acid (CPA), an inhibitor of endoplasmic reticulum Ca2+ pumps, but not by removal of extracellular Ca2+ ions. CPA also greatly diminished and slowed the receptor potential elicited by dim flashes. The results demonstrate a rapid release of Ca2+ ions that appears necessary for a highly amplified electrical response to dim flashes.
Key Words: cyclopiazonic acid, horseshoe crab, fluorescent indicator dye, receptor potential, phototransduction
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INTRODUCTION |
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Microvillar photoreceptors of invertebrates use the phophoinositide cascade to couple the absorption of light by rhodopsin to the activation of ion channels in the microvillar plasma membrane (
The role of light-induced Ca2+ release in excitation of invertebrate photoreceptors is uncertain and may depend on the species studied. In Drosophila photoreceptors, light-induced release of Ca2+ has been observed (
Measurement of Ca2+ at spots within a few microns of the photosensitive membrane by confocal fluorescence microscopy has permitted the detection of elevations of Cai that precede the electrical response to very intense focal stimulation (
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MATERIALS AND METHODS |
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Preparation of Photoreceptor Cells, Electrical Recording and Solutions
Ventral optic nerves were dissected as described by
Membrane potential was recorded through the micropipette used for pressure-injecting dye solutions. For some experiments, cells were impaled with a second electrode filled with 3 M KCl, through which current was supplied from a voltage-clamp amplifier (Axoclamp2A; Axon Instruments, Inc.).
Fluorescence Microscopy and Calibration of Illumination
Ventral nerves were viewed with an LSM 410 laser-scanning, inverted, confocal microscope (Carl Zeiss, Inc.) equipped with a 488-nm Ar-Kr laser (Uniphase Inc.) attenuated 300-fold and focused through a Neofluar x40/0.75 objective lens (for details, see
Photoreceptors were impaled with micropipettes containing 500 µM of the fluorescent Ca2+ indicator dyes, fluo-4 or Oregon green-5N (Molecular Probes, Inc.; dissociation constants determined to be 2 and 18 µM, respectively, in 400 mM KCl, 10 mM MOPS, pH 7.0) in a carrier solution containing 100 mM potassium aspartate, 10 mM HEPES, pH 7.0. 515 pressure injections of 110 pl were delivered into the cells. After loading the cells with dye, the site of origin of the Ca2+ release was determined. Photoreceptors were first viewed in the transmission mode of the microscope so as to determine the likely position of the light-sensitive rhabdomeral lobe (R-lobe). The position of the R-lobe was then confirmed by performing a line scan of fluorescence along the longitudinal axis of the cell. If the R-lobe was correctly identified, then, upon opening the shutter covering the laser beam, a delayed wave of increased fluorescence spread into the cell from the point at which the scanning line intersected the edge of the R-lobe (
Light intensities are expressed as "effective photons." One effective photon is the light energy required to photo-isomerize one rhodopsin molecule and so to elicit one quantal electrical response, a "quantum bump," from a dark-adapted photoreceptor (
Calibration of Fluorescence
Autofluorescence from cells not injected with indicator dye was observed to be negligible. Photomultiplier records of dye fluorescence, F, from injected cells were used to determine the mean fluorescence, Frest, during the latent period of the light response and the change in fluorescence, F = F - Frest, during the light response. For each cell, the saturated peak fluorescence, Fmax, during illumination by the unattenuated laser was also recorded. On the assumption that the dye is saturated by the peak elevation of Cai that follows flashes delivered by the unattenuated laser (see RESULTS), Cai can be estimated using the standard equation (
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(1) |
where Kd is the dissociation constant of the dye and Fmin is the fluorescence of the indicator with no Ca2+ bound. Two assumptions were adopted to obtain Fmin. For the low affinity indicator, Oregon green-5N, the dye was assumed to bind negligible Ca2+ at resting Cai, but to have a comparatively significant calcium-independent fluorescence. Fmin is then equal to Frest. In terms of the fluorescence changes recorded following illumination, Equation 1 becomes Equation 2:
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(2) |
or Equation 3:
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(3) |
where Fmax = Fmax - Frest.
For the high affinity indicator, fluo-4, calcium-independent fluorescence was assumed to be negligible compared with the fluorescence due to resting Cai. Fmin is then equal to zero. In terms of the fluorescence recorded after illumination, Equation 1 becomes Equation 4:
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(4) |
The protocol used for reconstructing elevations of Cai after dim flashes is similar to that adopted by
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By varying the time between dim and bright flashes, the time course of the elevation of Cai that followed the dim flash could be reconstructed (Fig 1), provided adequate time for dark adaptation was allowed between the paired flashes. To extend the time-window during which measurements of Cai could be made, the latent period of the response to the bright flash could be extended to 70150 ms by lowering the quantum efficiency of the cell through chemical bleaching of rhodopsin. In comparing the waveforms of the reconstructed calcium signals and the receptor potential in Fig 2, Fig 4, Fig 6, and Fig 10, it is important to note that the receptor potential shown is a representative response to the dim flash alone, recorded between presentations of the dual flashes. As Fig 1 illustrates, there was some variation in the latency of the receptor potential from flash to flash, which becomes significant for dim flashes delivering <1,000 effective photons. This variation reduces the accuracy with which the latency of the estimated elevations of Cai and that of the receptor potential can be compared. Stable recordings of dye fluorescence and membrane potential were generally obtained for up to 90 min after injection of the dye. With ~10 min between dual flash presentations required for dark adaptation in unbleached photoreceptors, reconstructions of elevations of Cai were usually limited to a maximum of 9 or 10 dual flash presentations.
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Synchronization of Traces
Membrane potential or current traces were digitally sampled at a rate of 1 kHz and stored on a computer, simultaneously with samples of the command pulses sent to the amplifier controlling the shutter placed in front of the laser beam. The shutter command pulses stored in these records were used to synchronize the current or voltage traces with the onset of fluorescence in the digitized records of photomultiplier output stored in the confocal microscope, after allowing 1.5 ms for shutter opening, as described in
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RESULTS |
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The Amplitude and Latency of the Elevation of Cai Is Graded with Flash Intensity
Photoreceptors were filled with the low affinity indicator, Oregon green-5N. A dual flash protocol (see MATERIALS AND METHODS) was used to reconstruct changes in dye fluorescence after dim flashes. Photoreceptors were dark adapted between presentations of dual flashes so that bumps of 15 mV could be recorded. For each cell, the saturated peak fluorescence, Fmax, was also recorded during illumination by a step of light from the unattenuated laser. After dim flashes, transient increases in dye fluorescence could be reconstructed that increased in peak amplitude with increasing flash intensity (Fig 2). The peak amplitude of the fluorescence saturated at Fmax for flash energies delivering >5 x 104 effective photons (Fig 3 A). This saturation is assumed to reflect that of the Ca2+-indicator dye rather than the value of Cai, since peak Ca2+ concentrations exceeding 150 µM have been recorded in response to a step of illumination by the unattenuated laser beam using a lower affinity dye, Calcium-Green 5N (Kd = 67 µM;
The Rising Edges of the Receptor Potential and of the Elevation of Cai Are Highly Correlated in Time
For flashes delivering <200 effective photons, the elevation of Cai recorded using Oregon green-5N was too small to reliably reconstruct its time course, and only the elevation of Cai at the peak of the receptor potential was sampled (but see below for fluo-4 signals). For more intense flashes, the time course of the initial elevation of Cai could be reconstructed (Fig 4). The peak receptor potentials after these flash intensities were all close to saturation, but their latencies greatly differed. Despite this difference in response latency, the rising edge of the reconstructed elevation of Cai was always approximately coincident with that of a representative receptor potential. For the dimmest flashes, the latencies of the response varied considerably from cell to cell (Fig 5 A), but for any given cell, the electrical signal and elevation of Cai were approximately coincident. As a measure of the latency of the elevation of Cai, we chose the time, Tc, Ca2+, taken for Cai to exceed a criterion of 2 µM, the smallest increase that could be reliably distinguished in individual reconstructions when using Oregon green-5N as the Ca2+ indicator dye. Tc, Ca2+ fell from an average of 141 ms for four cells illuminated by the dimmest flash to 21 ms as flash intensity increased (Fig 5 A). For this range of response latencies and light intensities, Tc, Ca2+ was approximately equal to the time, Tc, mV, taken to exceed an 8-mV criterion receptor potential (Fig 5 B). The relationship could be well described (r 2 = 0.987; n = 13) by the equation:
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(5) |
with t equal to 2.2 ± 6.4 ms. This time difference is not significant (P > 0.05).
For flashes delivering 50 or fewer effective photons, the change in Oregon green-5N fluorescence was insufficient to allow a detailed analysis of the time course of the response. A higher affinity indicator dye, fluo-4, was therefore used. The rising edge of the elevation of Cai induced by these dim flashes was also approximately coincident with the receptor potential (Fig 6A and Fig B; representative of recordings from three cells). Tc, Ca2+ and Tc, mV were both equal to 146 ms for criteria of 2 µM and 8 mV, respectively. In the same cell, the response to a step of illumination from the unattenuated laser beam also demonstrated coincidence of the receptor potential and the elevation of Cai (Fig 6 B). Tc, Ca2+ was 30 ms, and Tc, mV was 29 ms. The receptor potential and elevation of Cai were, therefore, approximately coincident in this cell for responses to illumination that differed in intensity by five orders of magnitude.
The elevation of Cai and receptor potential arise from the same stochastic process. Chemical bleaching of rhodopsin by hydroxylamine (see MATERIALS AND METHODS) reduced the quantum efficiency of photoreceptors by ~3 log10 U, while maintaining quantum bumps that were up to 10 mV in amplitude and of normal time course. Neither the latency of the responses delivering approximately the same number of effective photons nor the resting membrane potential was qualitatively altered by bleaching. This treatment reduced the effective intensity of the unattenuated laser from ~108 to ~105 effective photons/s, prolonging the latency of the response to continuous illumination from 2030 to 70150 ms. Because the laser illumination was unattenuated and continuous, the entire time course of an elevation of Cai accompanying a receptor potential could be determined and its latency correlated with that of the receptor potential. Thus, the problem of comparing elevations of Cai reconstructed from many flash responses with a representative receptor potential was eliminated.
After chemical bleaching, successive receptor potentials to unattenuated step illumination by the laser exhibited variation in their latent period (Fig 7). Variation in the latency of the receptor potential after dim flashes is thought to result from the stochastic nature of the underlying responses to single effective photons (t = 1.4 ± 1.14 ms. This time difference is not significant (P > 0.05).
To compare data from all five cells, the mean values of Tc, mV and Tc, Ca2+ recorded from a given cell were subtracted from those of individual signals (Fig 8 B). The resulting deviation scores of Tc, mV were equal to those of Tc, Ca2+ (r 2 = 0.829). Thus, if an elevation of Cai rose, for example, to exceed its criterion 10 ms earlier than its mean for that cell, it was highly probable that the electrical response would also exceed its criterion 10 ms earlier than its mean. This correlation indicates that the process generating the stochastic latency is shared by both signals.
While the results so far demonstrate that the timing of the electrical and Ca2+ signals are highly correlated, the absolute value of t does not indicate whether the Ca2+ signal "leads" or "lags" the electrical response of a cell.
t rather indicates the relative time for the two signals to reach criterion amplitudes and its value is therefore dependent upon the choice of those criteria. In further considering the significance of
t, we noted that it varied from +1.8 to -13 ms for the five cells studied, for criterion responses of 8 mV and 2 µM. We wished to determine whether this variation of
t between cells was due to systematic differences between recordings from different cells or due to noise inherent in estimating Cai. Fig 9 illustrates five responses each from two cells. To eliminate the variation in response latency from flash to flash, the time base of each step response has been normalized by subtracting Tc, mV. The two sets of responses show that the time course of the elevation of Cai relative to that of the receptor potential varies between the two cells in a systematic manner. The elevation of Cai was first detected 17.3 ± 4.5 ms before Tc, mV in Fig 9 A (arrow) and 7.4 ± 2.1 ms before Tc, mV in B (arrow) (detection was based on a criterion of two successive samples of Cai greater than 2 SD above the initial noise level). This variation in the relative timing of the signals from cell to cell, which may arise from small displacements of the confocal spot relative to Ca2+ release sites (see DISCUSSION), prevents us from determining an accurate relationship between Cai and the receptor potential amplitude. However, it is apparent from Fig 9 that the light-induced elevation of Cai is detectable at very small depolarizations. For the five cells, the mean depolarization was not significant (1.1 ± 1.2 mV; P > 0.05) at the time the light-induced elevation of Cai was first detected.
Elevations of Cai Can Be Measured to Flashes that Deliver as Few as 10 Effective Photons, When Quantal Fluctuations in Amplitude become Significant
After chemical bleaching, the increased latency of the response to the unattenuated laser allowed a greater time "window" in which to measure the elevation of Cai. Also, because the flashes used to elicit dye fluorescence were less effective, the time for dark adaptation between pairs of flashes was reduced from ~10 to ~2 min, allowing more samples to be taken while dye fluorescence levels were stable in the cell. These improvements allowed the measurement of elevations of Cai in cells filled with fluo-4 that accompanied extremely dim flashes, delivering ~10 effective photons, which demonstrated considerable stochastic variation in the amplitude and latency of individual receptor potentials (Fig 10 A). Although the accuracy of the comparison was limited to ~20 ms by variation in individual responses (Fig 10 B), the first appearance of a calcium signal was still approximately coincident with the appearance of the electrical response. In the same cell, the response to a step of illumination from the unattenuated laser beam also demonstrated coincidence of the receptor potential and the elevation of Cai (Fig 10 B). Similar elevations of Cai were obtained from two other chemically bleached cells.
The Elevation of Cai Arises from Release of Intracellular Ca2+, Not Influx
For bright steps of light, delivered by the unattenuated laser, the timing of the elevation of Cai, recorded from unbleached cells, relative to that of the electrical response, is unaffected by voltage clamping cells to their resting potential or by removal of extracellular Ca2+ (
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Reconstruction of the complete time course of elevations of Cai after dim flashes delivered to unbleached cells bathed in 0 Ca-ASW was not possible because of the progressive depletion of Ca2+ stores by the repeated bright flashes required to measure dye fluorescence (see below). However, up to five dual flashes could be delivered without greatly affecting the magnitude or latency of successive responses, so that a portion of the rising phase of elevations of Cai could be reconstructed (Fig 11 C). The magnitude of reconstructed elevations of Cai measured using Oregon green-5N after dim flashes and their timing relative to that of the receptor potential were similar to those recorded from cells bathed in ASW. Similar results were obtained from a total of four cells. The correlation between the latencies of the receptor potential and the elevation of Cai cannot, therefore, be ascribed to the entrance of Ca2+ ions through light- or voltage-activated channels in the plasma membrane.
Repeated Illumination in 0 Ca-ASW Increases the Latency and Slows the Rise Time of both the Elevation of Cai and the Receptor Potential
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The Elevation of Cai Is Necessary for Generating a Rapid, Highly Amplified Electrical Response
Bathing photoreceptors filled with fluo-4 in 0 Ca-ASW containing 100 µM CPA, an inhibitor of endoplasmic reticulum (ER) Ca2+ ATPase (
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Relationship between Cai and Inward Current
The above result, our failure to ascribe the elevation of Cai to influx of Ca2+, and the conclusions of previous work (see DISCUSSION) are consistent with the idea that the correlation between the timing of the light-induced elevation of Cai and inward current might result from the activation of an inward current by released Ca2+. As noted above, variation in the timing of the Ca2+ signal from cell to cell makes it impossible to define an accurate relationship between the estimated value of Cai and the receptor potential or the light-induced current. However, we thought it valuable to determine the approximate form of a process that might couple elevation of Cai to the receptor potential.
Fig 14 shows the mean elevation of Cai and inward current recorded from five bleached photoreceptors filled with fluo-4 that were voltage clamped to their resting membrane potentials and illuminated with a step of light from the unattenuated laser. For each cell, the time taken for the light-induced current to reach a criterion of -2 nA has been subtracted from the time base so as to compare the relative timing of Ca2+ and electrical signals, despite the variation in response latency. As with the voltage responses of Fig 9, the elevation of Cai was detectable at the earliest times of the electrical response to light. For three of the five cells individually, as well as for the mean data in Fig 9, elevation of Cai is detectable before significant inward current flow (detection based on a criterion of two successive samples >2 SD above the initial noise level). To relate the elevation of Cai to inward current flow, a simple model was assumed in which we ignore the small component that is not dependent on Ca2+ release during the rising edge of the response and assume that Ca2+ reversibly binds to the light-activated channel or an associated protein. The channel was assumed to be open for as long as Ca2+ is bound.
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For low [Ca2+], before saturation of the dye or inward current occurs, the rate of change of the mean inward current, iL(t), can be described by the differential equation:
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(6) |
Fig 14 shows a fit of Equation 6 to iL(t) obtained through numerical integration using the observed light-induced elevation of Cai, k'1 = 0.35 nA · µM-1 · ms-1 and k-1 = 0.2 ms-1. For constant [Ca2+], Equation 6 then describes a first-order process with a sensitivity of inward current to Cai of 1.75 nA · µM-1 and a time constant of 5 ms. Aside from parsimony, our choice of a linear relationship between [Ca2+] and iL is dictated by the following consideration. After the latent period, the rise of [Ca2+] with time during the light step of Fig 14 approximates to a linear ramp. Equation 6 then predicts that the current will also rise as a linear ramp after a brief delay, as is observed. Models that invoke a cooperative action of several calcium ions to activate the channel would predict a sigmoidal rise in current with time.
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DISCUSSION |
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Pharmacological experiments have indicated that light-induced release of Ca2+ is necessary, in Limulus photoreceptors, for a rapid, highly amplified initial response to dim flashes of light (
For a wide range of flash intensities and conditions, the detection of the electrical response of dark-adapted Limulus ventral photoreceptors is, within a few milliseconds, coincident with that of the elevation of Cai. For responses of five chemically bleached photoreceptors to steps of light, where an uninterrupted Ca2+signal could be recorded, the mean receptor potential was insignificant at the time that the elevation of Cai was detected. Elevation of Cai was detected in three of another five cells before significant inward current flowed under voltage clamp. These elevations of Cai appeared to result from the release of Ca2+ ions from intracellular stores, since they were undiminished by removal of extracellular Ca2+ ions, but were abolished by exposure to CPA. Thus, light-induced Ca2+ release precedes the generation of most, if not all, of the electrical response.
Implications for Models of Visual Transduction by Limulus Ventral Photoreceptors
Our observations necessitate a revision of a previous model of a role for Ca2+ release in phototransduction in Limulus photoreceptors.
The simplest explanation for the correlation between the elevation of Cai and the receptor potential is that light-induced elevation of Cai activates a component of the photocurrent (
In support of the proposal above, rapid Ca2+ release by flash photolysis of caged InsP3 can activate an inward current in Limulus ventral photoreceptors within 2.5 ± 3.3 ms of the detection of the InsP3-induced elevation of Cai (
Since treatment with CPA abolishes the large quantum bumps that comprise the response of the cell to very dim illumination (
The Time to Release Ca2+ May Limit the Temporal Accuracy of Visual Transduction
Previous attempts to demonstrate an elevation of Cai that precedes or accompanies the rising edge of the electrical response using aequorin or Arsenazo III as an indicator were not successful (
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Footnotes |
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1 Abbreviations used in this paper: ASW, artificial sea water; CPA, cyclopiazonic acid; ER, endoplasmic reticulum; InsP3, inositol (1,4,5) trisphosphate; R-lobe, rhabdomeral lobe.
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Acknowledgements |
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We thank Dr. Alain Dabdoub and Ms. Monika Deshpande for critical reading of the manuscript and Dr. Ian Mather of the Animal and Poultry Science Department, University of Maryland, for the use of the confocal microscope.
This work was supported by National Institutes of Health EY07743.
Submitted: 29 December 1999
Revised: 20 April 2000
Accepted: 21 April 2000
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