Correspondence to: Mary T. Lucero, Department of Physiology, University of Utah, 410 Chipeta Way, Room 155, Salt Lake City, UT 84108-1270. Fax:801-581-3476 E-mail:mary.lucero{at}m.cc.utah.edu.
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Abstract |
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Olfactory receptor neurons (ORNs) from the squid, Lolliguncula brevis, respond to the odors L-glutamate or dopamine with increases in internal Ca2+ concentrations ([Ca2+]i). To directly asses the effects of increasing [Ca2+]i in perforated-patched squid ORNs, we applied 10 mM caffeine to release Ca2+ from internal stores. We observed an inward current response to caffeine. Monovalent cation replacement of Na+ from the external bath solution completely and selectively inhibited the caffeine-induced response, and ruled out the possibility of a Ca2+-dependent nonselective cation current. The strict dependence on internal Ca2+ and external Na+ indicated that the inward current was due to an electrogenic Na+/Ca2+ exchanger. Block of the caffeine-induced current by an inhibitor of Na+/Ca2+ exchange (50100 µM 2',4'-dichlorobenzamil) and reversibility of the exchanger current, further confirmed its presence. We tested whether Na+/Ca2+ exchange contributed to odor responses by applying the aquatic odor L-glutamate in the presence and absence of 2',4'-dichlorobenzamil. We found that electrogenic Na+/Ca2+ exchange was responsible for ~26% of the total current associated with glutamate-induced odor responses. Although Na+/Ca2+ exchangers are known to be present in ORNs from numerous species, this is the first work to demonstrate amplifying contributions of the exchanger current to odor transduction.
Key Words: electrogenic, dichlorobenzamil, chemoreception, sodiumcalcium exchange, cephalopod
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INTRODUCTION |
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Calcium plays multiple roles in olfactory transduction. In addition to contributing to the initial transduction current (
Both Ca2+ pumps and Ca2+ exchangers are used to regulate intracellular Ca2+. Two classes of electrogenic Ca2+ exchangers have been cloned, the Na+/Ca2+, K+ exchanger (NCKX) (
In the olfactory system, sodiumcalcium exchange has been localized, both by calcium imaging and immunocytochemistry, to the dendritic knob (and possibly the cilia) of rat ORNs, where it is presumed to clear calcium from the olfactory cilia and dendritic knob after odor stimulation (
Squid ORNs can be either excited or inhibited by odors (
We have used nystatin-perforated patch and whole-cell voltage-clamp recordings to characterize electrogenic sodiumcalcium exchange activity in squid ORNs. Forward activity of this exchanger is completely inhibited by removing external Na+, but is not affected by removal of internal or external K+. NCX currents are blocked by 2',4'-dichlorobenzamil (DCB), an inhibitor of sodiumcalcium exchange (
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MATERIALS AND METHODS |
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Cell Preparation and Culture Conditions
The methods for cell dissociation were similar to those described in
Solutions
The external bath and internal pipette solutions used in these experiments are listed in Table 1 and Table 2. The external and internal solutions were set to an osmolarity of 780 mOsm and a pH of 7.4 or 7.2, respectively. The culture medium consisted of Leibovitz's L-15 (GIBCO BRL) supplemented with salts to bring the osmolarity to 780 mOsm, 2 mM HEPES, pH 7.6, 2 mM L-glutamine, 50 IU ml-1 penicillin G, and 0.5 mg ml-1 streptomycin. Nystatin stock solution contained 1 mg nystatin/20 µl DMSO; nystatin internal solution contained 3 µl nystatin stock + 2 µl 10% pluronic acid ml-1 internal solution. All internal solutions were kept on ice throughout the experiments.
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Chemicals
All chemicals were obtained from Sigma-Aldrich except for DCB, which was obtained from Molecular Probes. DCB was dissolved in DMSO as a 50-mM stock solution before dilution to 50 or 100 µM in ASW.
Nystatin Perforated-Patch Voltage-Clamp Recordings
Nystatin voltage- and current-clamp experiments were essentially similar to those described in resistance electrodes pulled from thick-walled borosilicate filament glass (Sutter Instrument Co.) were filled with nystatin internal solution. Fresh nystatin internal solution was made every 2 h and nystatin stock was remade every 5 h. Gentle suction was applied to form a gigaohm seal. Recordings were made ~520 min after seal formation. Bath solutions were perfused through the recording chamber at a rate of 12 ml min-1. Test solutions were delivered with an SF-77 rapid solution changer (Warner Instrument Corp.). The application of test solutions was calibrated with an open pipette. There was a delay of ~90 ms between the beginning of the electronic stimulus and the current recorded by the open pipette. We did not correct the data for this delay. A 3-M KCl agar bridge was used to ground the recording chamber.
Whole-Cell Voltage-Clamp Recordings
Whole-cell voltage-clamp recordings were similar to the nystatin patch recordings. The same 25-M resistance electrodes were filled with either Na+-gluconate internal containing Mg2+-ATP or with Li+-internal solution. The electrode tip was lowered onto the soma of the ORN and gentle suction was applied to form a gigaohm seal. Once the seal was formed, more suction was applied to rupture the membrane patch and achieve whole-cell access. Bath and test solutions were delivered as described for nystatin-perforated patch recordings.
Data Acquisition
Voltage-clamp and current-clamp data were acquired with an Axon Instruments 200A patch clamp amplifier (TL-1-125 Interface; Axon Instruments, Inc.) and a 486, 33 MHz computer using either PClamp 5.6 or Axotape 2.0.2. The data in Fig 1, Fig 2, and Fig 3 B were sampled at 250 Hz and filtered off line with a digital eight-pole lowpass Bessel filter (Clampfit 8; Axon Instruments, Inc.) using a -3 dB filter cutoff frequency of 35 Hz. The data in Fig 3 A, 5, and 6 were sampled at 500 Hz and digitally filtered off line with a -3 dB filter cutoff frequency of 50 Hz. The data in Fig 4 were acquired at 10 kHz and filtered on line with a low pass four-pole Bessel filter cutoff at 5 kHz. Data for capacitance and series resistance (Rs) measurements were sampled at 100 kHz and also filtered on line at 10 kHz (data not shown). The Rs of nystatin-perforated patched cells averaged 39 ± 13 M (SD; n = 18). Approximately 6075% of Rs was electrically compensated. The voltage errors associated with the remaining Rs as well as liquid junction potentials were corrected for off line as described in
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These experiments comply with NIH publication 86-23, "Principles of Animal Care," revised 1985, and with the current laws of the Unites Stated regarding animal research.
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RESULTS |
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Caffeine Activates a Sodium-dependent Inward Current
Ca2+-imaging experiments have shown that caffeine releases calcium from internal stores in squid ORNs (
Replacing external Na+ with Li+ also eliminated the caffeine-induced inward current (Fig 1 D). Fig 1C and Fig D, shows traces from a single squid ORN treated with 10 mM caffeine in normal ASW and Li+ ASW, respectively. In this cell, the maximum amplitude of the current was reduced from -807 to -22 pA. In normal ASW, these caffeine-induced currents averaged -788 ± 316 pA (SD; n = 5) and had an average current density of 8 ± 1 pA/pF at -50 mV. However, in Li+ ASW, the size of the current was significantly reduced by 94% to -44 ± 50 pA and a density of 0.4 ± 0.3 pA/pF (SD; n = 5; paired t test, P < 0.01; Fig 1 E). Inhibition by both Tris+ and Li+ indicates that the caffeine-induced inward current is Na+ dependent, as would be expected for forward Na+/Ca2+ exchange rather than a Na+-selective conductance such as a Ca2+-activated cation channel or a cyclic nucleotidegated channel. The presence or absence of K+ in the internal solution did not affect the caffeine-induced current (Fig 1 A), suggesting that the NCKX is not contributing to the caffeine-induced responses.
DCB Inhibits the Caffeine-activated Current
The dependence of caffeine-activated currents on external Na+, along with caffeine's ability to liberate internal calcium stores in squid ORNs (
Time Course of INCX
In squid ORNs, odor responses peak within 300400 ms (
INCX Is Reversible
Some Na+/Ca2+ exchangers are capable of acting in either forward or reverse mode (, SD; n = 11), the intracellular and pipette solutions were allowed to equilibrate for 13.5 ± 7.6 min before the external bath solution was switched from ASW to Tris+ ASW. The combination of high internal sodium, low internal calcium, zero external sodium, and 10 mM external calcium was expected to stimulate reverse Na+/Ca2+ exchange, resulting in extrusion of Na+, uptake of Ca2+, and an outward exchanger current. Under these conditions, the removal of external sodium stimulated outward currents (seen as a reduction in the steady state inward leak current) that we attribute to reverse Na+/Ca2+ exchange (Fig 4 A). As expected, the inward current reduction observed upon removal of external Na+ was smaller when a Li+ internal solution was used (Fig 4 B; Rs = 34 ± 12 M
; equilibration time = 3.9 ± 1.9 min; n = 8). To quantify these results, we calculated the percent decrease in the magnitude of the resting inward current obtained when the external bath solution was switched from ASW to Tris+ ASW. With the Li+ internal solution, the steady state inward current was reduced by 26 ± 13% (SD; n = 9), a significantly smaller decrease than the 42 ± 13% (SD; n = 11) reduction measured with high Na+ internal solution (Independent Student's t test; P < 0.05; Fig 4 C). Presumably, a longer more complete equilibration of the Li+ internal would have further reduced the effect on the inward current. Indeed, the cell shown in Fig 4 B had equilibrated and the switch to Tris+ ASW had very little effect. These results indicate that reverse Na+/Ca2+ exchange can be stimulated by high internal Na+ concentrations combined with Na+ free external solution, and that reverse INCX can be reduced by replacing internal Na+ with Li+.
INCX Amplifies Odor-induced Currents
To determine if INCX plays a role in olfactory transduction, we tested its effect on glutamate-activated currents. Glutamate activates a nonselective, calcium-permeable conductance in squid ORNs (
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Although 2'4'DCB has been established as an inhibitor of Na+/Ca2+ exchange, a closely related compound, 3'4'DCB can inhibit cyclic nucleotidegated channels (
To further confirm the specificity of DCB, we applied it during glutamate responses in Li+ ASW. Under these conditions, there should be no Na+/Ca2+ exchange because of the lack of external sodium. Thus, any reduction of the glutamate-activated currents would be due solely to block by DCB. Fig 6A and Fig B, shows glutamate-induced current traces from a single squid ORN in Li+ ASW in the absence and presence of DCB, respectively, and show that DCB has no effect on the size of glutamate-activated currents. The current responses from six cells were normalized to the response to glutamate alone and plotted in Fig 6 C. In Li+ ASW, the magnitude of the responses to glutamate in the presence of DCB was 98 ± 14% of the responses to glutamate, a difference that was not significant at the P > 0.05 level. These results confirm that Na+/Ca2+ exchange acts to augment or amplify odor responses to glutamate in squid ORNs.
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DISCUSSION |
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INCX Is Present in Squid ORNs
We have identified a sodiumcalcium exchanger in squid ORNs that is activated by increases in intracellular calcium, dependent upon external sodium, inhibited by DCB, a blocker of sodiumcalcium exchange, and which amplifies glutamate-induced inward currents. There was a significant delay in the onset of INCX activated by caffeine compared with odor responses. The sequential steps required for caffeine-induced INCX responses could cause this delay. First, caffeine must reach the cell and diffuse through the plasma membrane and the cytosol to reach intracellular Ca2+ stores. Then caffeine binds and activates ryanodine receptors that are presumably present and responsible for liberating calcium stores. Finally, the released calcium must diffuse through the cytosol to activate the sodiumcalcium exchanger proteins. These steps are contrasted with odor transduction, where, presumably, all of the transduction machinery is located in very close proximity, minimizing diffusion times and resulting in faster kinetics. With regard to the amplification of glutamate responses by INCX, there was no delay seen for the portion of the current attributed to NCX. The glutamate-induced current and INCX were concurrent (see Fig 5). These results suggest that some NCX proteins are located in very close proximity to the transduction channels for glutamate-induced odor responses, and that the delay between caffeine application and INCX is due to the several diffusion and binding steps mentioned above and not to any property of the sodiumcalcium exchanger itself. In support of this hypothesis, our recent immunological study using a polyclonal antibody against the cloned squid NCX (NCX-SQ1) showed specific staining localized to the cilia of the pyriform cell type used in the present studies (
Ionic Dependence of INCX
We have shown that forward Na+/Ca2+ exchange in squid ORNs is blocked by the replacement of external Na+ with either Tris+ or Li+. In addition, there does not appear to be any dependence upon internal K+. In all of the experiments except for those presented in Fig 4, there was no K+ present in the internal pipette solutions. These ionic requirements are consistent with the NCX type Na+/Ca2+ exchangers, including the mammalian cardiac exchanger, NCX1, and the recently cloned NCX-SQ1 from squid (
Reversal of INCX
In addition to forward Na+/Ca2+ exchange stimulated by caffeine application, we have also demonstrated reverse Na+/Ca2+ exchange in squid ORNs. This, again, is consistent with results seen for other NCX-type exchangers and with the squid Na+/Ca2+ exchanger, NCX-SQ1 (
Amplification of Odor Responses
Olfactory receptor potentials in several species have been shown to consist of at least two current responses, an initial transduction current, followed by (or coupled with) an amplification current. In vertebrate ORNs, calcium-activated chloride currents amplify the initial transduction current (
The reduction in the glutamate-induced current in the presence of Li+ or DCB was not due to a buildup of intracellular Ca2+ acting directly on the transduction machinery because coapplication of glutamate and DCB produced the same inhibition as a 1 min preincubation in DCB. In addition, we showed that in the absence of NCX, DCB had no effect on the glutamate-induced current (Fig 6). Thus, the component of glutamate-induced current inhibited by DCB or Li+ application appears to be INCX and not an indirect effect of the experimental conditions.
In frog, sodiumcalcium exchange appears to be involved in terminating olfactory responses. By removing [Ca]i, the size and duration of ICl(Ca) is reduced. Conversely, the duration of ICl(Ca) is prolonged when sodiumcalcium exchange is blocked by eliminating external Na+ (
Use of NCX during glutamate responses in squid ORNS results in a 1.5x amplification of the original Ca2+ signal. This observation can be verified algebraically. We start with the simple equation:
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(1) |
where IGlutotal = the total current recorded during glutamate application, IGluCa2+ is the glutamate-induced current carried by Ca2+ influx through the transduction channel, IGlu+ is the glutamate-induced current carried by monovalent cations through the transduction channel, and INCXCa influx is the net inward current of the exchanger activated by Ca2+ influx. If we take the extreme case where Ca2+ carries all of the current that enters the transduction channel during a glutamate response, then IGlu+ reduces to zero and Equation 1 becomes:
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(2) |
For every 2+ charges that enter the cell as Ca2+, 3+ charges enter as Na+ on NCX, resulting in a 1.5x amplification of the Ca2+ signal. Assuming that the only Ca2+ available to the exchanger is via influx, then
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(3) |
Since under the hypothetical conditions of a Ca2+-selective transduction channel, two thirds of IGlutotal is carried by Ca2+, we can substitute % values into Equation 2, where (Equation 4):
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(4) |
This means that if all of the current through the transduction channel were carried by Ca2+, then total block of INCX would reduce IGlutotal by 33.3%. If reduction of IGlutotal was <33.3% then, by substituting Equation 3 into 1 and rearranging we see that the contribution of monovalent cations (IGlu+) to the total glutamate-induced current is (Equation 5):
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(5) |
If block of INCX reduces IGlutotal by >33.3%, then, in addition to Ca2+ influx, Ca2+ released from intracellular stores must contribute to INCX (INCXCastores) and the total INCX (INCXtotal) becomes (Equation 6):
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(6) |
Rearranging and including contributions from monovalent cations gives the final form of the equation describing the glutamate-induced current (Equation 7):
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(7) |
We showed that regardless of whether INCX was blocked by DCB or not supported by Li+ replacement of external Na+, IGlutotal was reduced on average by 2631%. These findings indicate that the majority (70% or more) of the current through the glutamate-induced transduction channel is carried by Ca2+, and that there is a small contribution (22% or less) by monovalent cations. If we look at individual cells, we see that in some cells, INCX total contributes >40% of the current. In these cases, we suggest that Ca2+ released from intracellular stores is contributing to the total Ca2+ available to the exchanger and further amplifying the current. In general, the contribution of Ca2+ by store release was modest and only observed in a subset of cells (4/18 cells in DCB, 2/5 cells in Li+). Thus, activation of NCX during glutamate responses appears to be mainly dependent on Ca2+ influx through a glutamate-activated transduction channel (IGluCa2+). These observations correlate well with our earlier studies showing that the glutamate-induced current in squid ORNs has a much higher selectivity for Ca2+ over Na+ or K+ (
In addition to depolarizing odor responses, squid ORNs respond to some odors (all aversive so far) with hyperpolarizing responses (
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Footnotes |
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1 Abbreviations used in this paper: ASW, artificial sea water; DCB - 2',4' dichlorobenzamil; ext, external; int, internal; NCKX, Na+/Ca2+, K+ exchanger; NCX, sodium calcium exchange; ORN, olfactory receptor neuron.
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Acknowledgements |
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We thank J.D. Lucero, T. Dang, and Dr. C. Hegg for technical assistance and the National Resource Center for Cephalopods (Galveston, TX) for providing squids. We also thank Drs. W.C. Michel, H.M. Brown, D. Piper, and K. Spitzer for helpful comments on the manuscript.
This work was supported by National Institutes of Health (NIH) National Institute on Deafness and Other Communication Disorders grant DC02587 to M.T. Lucero.
Submitted: 25 October 1999
Revised: 25 April 2000
Accepted: 27 April 2000
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