Evidence for the Involvement of Inositol Trisphosphate but Not Cyclic Nucleotides in Visual Transduction in Hermissenda Eye*

Manabu SakakibaraDagger §, Hiroko Inoue, and Tohru Yoshioka

From the Dagger  Department of Biological Science and Technology, School of High Technology for Human Welfare, Tokai University, Numazu 410-03, Japan and the  Department of Molecular Neurobiology, School of Human Sciences, Waseda University, Tokorozawa 359, Japan

    ABSTRACT
Top
Abstract
Introduction
Procedures
Results
Discussion
References

Although several second messengers are known to be involved in invertebrate photoresponses, the mechanism underlying invertebrate phototransduction remains unclear. In the present study, brief injection of inositol trisphosphate into Hermissenda photoreceptors induced a transient Na+ current followed by burst activity, which accurately reproduced the native photoresponse. Injection of Ca2+ did not induce a significant change in the membrane potential but potentiated the native photoresponse. Injection of a Ca2+ chelator decreased the response amplitude and increased the response latency. Injection of cGMP induced a Ca2+-dependent, transient depolarization with a short latency. cAMP injection evoked Na+-dependent action potentials without a rise in membrane potential. Taken together, these results suggest that phototransduction in Hermissenda is mediated by Na+ channels that are directly activated by inositol trisphosphate without mobilization of cytosolic Ca2+.

    INTRODUCTION
Top
Abstract
Introduction
Procedures
Results
Discussion
References

There is abundant evidence that the phosphoinositide cascade is involved in invertebrate phototransduction; however, the specific roles of inositol trisphosphate (IP3)1 and/or Ca2+ in visual excitation have not yet been established (1-3). The involvement of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C (PLC) in the generation of IP3 in photoreceptors of Limulus (4, 5), squid (6-8), Drosophila (9-12), and Hermissenda (13) is supported by several lines of biochemical and biophysical evidence. In particular, the photoresponse in Drosophila was found to be absolutely dependent on PLC activity. Until recently, it was thought that IP3 is the second messenger involved in the photoresponse in invertebrates because a brief injection of IP3 mimicked the quantal response to light (4, 5) and IP3-induced Ca2+ release resulted in membrane depolarization in the Limulus ventral photoreceptor (14) by activating Ca2+/Na+ exchange (15, 16).

More recent evidence, however, indicates that the mechanism is more complex. For example, many contradictions arise if Ca2+/Na+ exchange is assumed to be the only mechanism involved in phototransduction: 1) the light response precedes the rise in Ca2+ (1), 2) excitation occurs in the absence of an IP3-induced increase in intracellular Ca2+ in Limulus (17), 3) abrupt Ca2+ elevation using caged Ca2+ fails to activate any channels in Drosophila photoreceptor membrane (18), and 4) the Drosophila mutant deficient in IP3 receptors still produces the native photoresponse (19). Furthermore, cGMP induces an inward current in photoreceptor cells in Limulus (20) and Drosophila (21) and activates channels directly in excised patches of molluscan microvilli membrane (1, 22). It is still uncertain, however, whether intracellular cGMP concentration is altered by light (23-25). Adding to the complexity of the system is the possibility of second messenger cross-talk between IP3, Ca2+, and cyclic nucleotides to activate intracellular chemical cascades (26).

Hermissenda provide an ideal animal model in which to examine invertebrate visual transduction mechanisms. The photoreceptors are relatively large (50 µm in diameter) and are well characterized electrophysiologically (27-35). They possess two types of photoreceptors: A and B (28, 29). Photoreceptor B responds to a bright flash with a complex potential change involving an initial depolarization, a hyperpolarization, and a depolarizing tail, corresponding to a rapid and transient Na+ conductance increase, a slower increase in K+ permeability, and a delayed decrease in K+ permeability, respectively (32). The initial Na+ current appears to be the primary phototransduction event because 1) following light adaptation, light flashes produce only the hyperpolarization component (32) and 2) the hyperpolarization is Ca2+-dependent (33) and Hermissenda photoreceptors respond to single photons even in TTX containing, low Ca2+ high Mg2+ solution (34). Our previous work also indicates that the photoresponse may be generated through a TTX-resistant Na+ channel (36).

The present study focuses on investigating the second messengers underlying the initial Na+ current component of the photoresponse. Recently, channels directly gated by IP3 have been described in other cell lines (37, 38), including Na+ channels in rat megakaryocytes (39). This raises the possibility that the native photoresponse in Hermissenda is generated by an IP3-gated Na+ channel. To further characterize the role of IP3 and the possible role of cGMP, cAMP, and Ca2+ in invertebrate phototransduction, the effects of injection of these second messengers were examined electrophysiologically in Type B photoreceptors of Hermissenda.

    EXPERIMENTAL PROCEDURES
Top
Abstract
Introduction
Procedures
Results
Discussion
References

Electrophysiological Assay-- Hermissenda crassicornis obtained from the Sea Life Supply (Sand City, CA) were maintained in artificial sea water (ASW) at 14 °C. Type B photoreceptors were dissected in ASW (430 mM NaCl, 10 mM KCl, 50 mM MgCl2, 10 mM CaCl2, and 10 mM Tris-HCl, pH 7.4). Dissection and intracellular recording were performed as described previously (13). cGMP, cAMP, and IP3 (Sigma) were dissolved in intracellular solution (67 mM sodium acetate, 400 mM potassium gluconate, 10 mM MgCl2, 10 mM HEPES, 1.5 mM CaCl2, 1.5 mM EGTA, pH 7.4) at a concentration of 1 mM. Isobutylmethylxanthine (IBMX) was dissolved in Me2SO and diluted with intracellular solution to 1 mM. The intracellular solution alone or with Me2SO had no effect on the photoresponse. A microelectrode containing the drug was inserted into the photoreceptor cell, and the drug was injected using a pressure injector (Medical System, Greenvale, NY) at 30.0 p.s.i. for 200 ms. In some experiments the drug was iontophoresed into the photoreceptor for at least 3 min with DC current of 2.5 nA, after 10 min of dark adaptation. A photoresponse was elicited every 90 s during the entire experimental period to keep the adaptation level constant. Unattenuated light of 34.0 µW/cm2 at 550 nm delivered from a halogen lamp source was administered to the underside of the preparation.

Assay of PIP2 Breakdown and PLC Activity-- Isolated Hermissenda eyes were incubated in 10 µl of ASW containing 10 µCi of [3H]inositol (Amersham International) in darkness at 23 °C for 16 h. Then one eye of each pair was exposed to light for 30 s. The incubation was stopped by adding chloroform/methanol/12 N HCl (200:100:0.75), and PIP2 standard was added as a carrier and to aid in the identification of the lipids. Phospholipids were extracted and separated by thin layer chromatography as described previously (9). Lipids were visualized with I2 vapor, and appropriate bands were scraped and counted. PIP2-PLC activity was assayed using the particulate fraction obtained from the Hermissenda circumesophageal nervous system as described previously (13).

    RESULTS
Top
Abstract
Introduction
Procedures
Results
Discussion
References

Comparison between the Photoresponse and the IP3-induced Response-- The IP3-evoked response was highly dependent on the distance between the injection site and the rhabdomeric membrane, the light-sensitive region (Fig. 1a). Immediately after IP3 was injected into a microvilli of the Type B photoreceptor close to the rhabdomeric membrane, a large transient response was observed (Fig. 1a). No response was observed after injection approximately 10 µm away from the photosensitive region. The latency of the photoresponse decreased with increasing light intensity (Fig. 1b). With low light intensity, the rate of rise and the peak amplitude of the photoresponse were low. With increased light intensity, a more complex response was observed, consisting of an initial depolarization, a hyperpolarization, and a depolarizing tail, consistent with previous reports (32). The first component was because of a rapid and transient Na+ conductance increase, the hyperpolarization was because of a slow increase in K+ permeability, and the depolarizing tail was because of a slow decrease in K+ permeability (33). The Na+ current was a graded response, consistent with previous observations in Hermissenda (36) and photoreceptors of other species (40, 41). The spontaneous firing activity superimposed on the photoresponse is known to arise from the distal portion of the axon and is not involved in the visual transduction process (31). Many characteristics of the response to IP3 injection were similar to the response to a relatively weak light flash, including the latency and the generation of action potentials (Fig. 1c). Simultaneous light flash and IP3 injection were additive (Fig. 1d). Furthermore, both responses were completely inhibited upon removal of extracellular Na+ (Fig. 1d). Similar to the native photoresponse, the IP3-evoked response was not dependent on the extracellular Ca2+ concentration (data not shown). Successive injection of IP3 resulted in a broadening and a decrease in the amplitude of the first peak and a higher frequency of spontaneous firing. This response mimicked the photoresponse to flickering light stimulation (Fig. 1e). Flickering light stimulation elicited an increase in the Na+ conductance and a decrease in the hyperpolarization.


View larger version (27K):
[in this window]
[in a new window]
 
Fig. 1.   Light- and IP3-induced responses from the Type B photoreceptor of Hermissenda. a, schematic drawing of an eye composed of five photoreceptors with the positions of the electrodes. The rhabdomeric membranes are indicated by the black portions. The lightly shaded portion indicates the Type B photoreceptor. IP3 injections were applied via electrodes placed in microvilli of the Type B photoreceptor at position 1, close to the rhabdomeric membrane, and position 2, approximately 10 µm away. The traces are electrical recordings of the response of the photoreceptor to IP3 injection. b, photoresponses to increasing intensities of light (unattenuated 200-ms light flash of 34 µW/cm2 at 550 nm) from -6 log to -1 log units. c, responses of the same cell to a light flash and an IP3 injection. The intensity of light was adjusted to obtain a response amplitude comparable with that of the response to the IP3 injection. The duration of both the light flash and the IP3 injection was 200 ms; the former was controlled by an electromagnetic shutter, and the latter was controlled by a pressure injector with a monitor of the pressure at the end of the electrode. d, the IP3-induced response (dotted line) and the response to light were additive. The additive response (continuous line) was obtained by a simultaneous IP3 injection and light flash, of which the intensity was attenuated to produce a small photoresponse. Note that the IP3-induced response was abolished in Na+-free ASW. e, the response to repetitive injection of IP3 mimicked the response to flickering light (bottom panel).

Effects of Ca2+ on the Photoresponse-- To examine whether a transient increase in intracellular Ca2+ activated the visual transduction channel, Ca2+ (1 mM) was injected into the photosensitive region of the Type B photoreceptor. In contrast to results obtained in Limulus (14), injection of Ca2+ alone did not induce any significant response (Fig. 2a), but when a light flash was applied to the photoreceptor preinjected with Ca2+, the amplitude of the initial peak of the photoresponse and the hyperpolarization were potentiated (Fig. 2b). This response was similar to the response to an intense light flash shown in Fig. lb.


View larger version (14K):
[in this window]
[in a new window]
 
Fig. 2.   Ca2+ facilitated the native photoresponse. a, Ca2+ injection alone (1 mM for 200 ms) did not produce a significant response. b, the light-induced response amplitude increased 1.5 times compared with control, and a significant after-hyperpolarization (arrow) appeared after the injection of Ca2+. The resting membrane level is indicated by a dotted line. c, the effect of 1 mM BAPTA on the photoresponse. Photoresponse before BAPTA injection (top panel), 3 min later (middle panel), and 6 min later (bottom panel). The initial depolarizing photoresponse gradually diminished and then reversed to a hyperpolarization.

When BAPTA (a Ca2+ chelator; 1 mM) was injected intracellularly prior to a light flash, the latency of the photoresponse increased, and the amplitude decreased (Fig. 2c) and was eventually completely inhibited (data not shown). The decrease in the initial peak of the response may be because of a decline in PLC activity dependent on the levels of cytosolic Ca2+.

Next we examined the involvement of PLC in the photoresponse by injecting PLC inhibitors such as aminoglycoside antibiotics and polyamines. Our previous data indicate that neomycin completely inhibits PLC activity in Hermissenda at concentrations higher than 0.1 mM and spermine inhibits PLC activity at concentrations higher than 0.5 mM (13). These suppressive effects are also carefully reconfirmed in this experiment (data not shown). Iontophoretic injection of 1 mM neomycin into Type B photoreceptors caused the response to light to be almost completely abolished 90 s after the injection without a change in the resting membrane potential (Fig. 3a). The amplitude of the initial depolarization recovered gradually but incompletely. The amplitude of the depolarizing tail did not recover within 5 min after injection (data not shown) but recovered completely within 18 min. Gentamicin and higher concentrations of neomycin produced more prolonged inhibition of the photoresponse (data not shown). Injection of spermine (1 mM) produced a minor suppressive effect on the photoresponse without changing the resting membrane potential (Fig. 3b). The amplitude of the initial depolarization was suppressed to 50% but recovered to 90% of the control response within 10 min after the injection (Fig. 3b). Injection of spermidine (1 mM), a weaker inhibitor of PLC, produced a smaller (less than 40%) inhibition of the photoresponse (data not shown). Inhibition of the hyperpolarization and the depolarizing tail of the photoresponse by spermine and spermidine is consistent with the fact that these compounds are Ca2+-activated K+ channel blockers (42).


View larger version (26K):
[in this window]
[in a new window]
 
Fig. 3.   Modulation of the native photoresponse to aminoglycosides, polyamines, and IBMX. a and b, responses were suppressed by the injection of neomycin (a, 1 mM) and spermine (b, 1 mM). c, IBMX reduced the amplitude of the initial depolarization of the photoresponse. The reduced response completely recovered 540 s after IBMX injection. d, IBMX reduced the light-induced inward current measured using two microelectrode voltage clamps (36) at a holding potential of -60 mV. The numbers on the left represent the time in seconds after the injection. The bottom panel shows the recovery of the response at 18, 10, 9, and 9 min from a to d, respectively.

IBMX is a well characterized phosphodiesterase inhibitor and also a potent blocker of PIP2 synthesis (43). Iontophoretic injection of IBMX transiently suppressed the initial depolarization and the depolarizing tail and was completely reversible within 9 min (Fig. 3c). IBMX also reduced the light-induced Na+ current in a similar manner (Fig. 3d). These results resemble those obtained from the photoreceptor cells of octopus (43) and Limulus (23). Other inhibitors of phosphoinositide metabolism, such as lithium and R59022, also decreased the initial depolarization (13). The order of potency of suppression of the initial depolarization is as follows: gentamicin > neomycin > LiCl > spermine > R59022 > spermidine.

Effects of Cyclic Nucleotides on the Photoresponse-- Although a significant change in the concentration of cyclic nucleotides in invertebrate photoreceptors during light irradiation has not been observed (25, 43), we tested the possibility that these cyclic nucleotides are involved in visual transduction (44). Intracellular pressure injection of 1 mM cAMP generated a train of action potentials without a significant change in resting membrane potential (Fig. 4a). Consistent bursts of action potentials were observed in response to successive injections of cAMP (Fig. 4b). Successive bursts were not significantly different from the first burst, indicating that the effects of the injection were transient, unlike the effects of IP3, Ca2+, or BAPTA injection. The responses to cAMP injections were abolished in Na+-free ASW, similar to the response to IP3 injection (Fig. 4b). The response to cAMP in Hermissenda also differed from that in Limulus (44), suggesting further that the phototransduction mechanism in Hermissenda is different from the ventral eye in Limulus.


View larger version (21K):
[in this window]
[in a new window]
 
Fig. 4.   Responses induced by 1 mM cAMP injection. a, comparison between the light- and cAMP-induced response. cAMP injection evoked a train of action potentials without a change in resting membrane potential. b, repetitive injection of cAMP-induced responses that did not change significantly with successive injections.

Injection of cGMP-induced transient depolarizing responses that were dependent on the distance between the photosensitive area and injection site (Fig. 5a). Interestingly, only the amplitude of the response, not the latency, was dependent on this distance. In contrast to previous observations in Limulus (20) and Drosophila (21), the transient response to injection of cGMP occurred without any change in the resting potential. The time course of the cGMP-induced response was different from that of the native photoresponse; simultaneous stimulation with cGMP injection and light flash resulted in a double-peaked response (Fig. 5b).


View larger version (9K):
[in this window]
[in a new window]
 
Fig. 5.   cGMP-induced responses. a, cGMP injection evoked a transient depolarization without any generation of action potentials. The numbers on the left represent the distance in microns that the injection electrode was advanced from the penetration site, position 2 of Fig. 1. b, comparison of the responses to cGMP injection and light flash. The latency of the response to cGMP was much shorter than that of the response to light.

We examined the effect of long term iontophoretic injection of cGMP on the photoresponse and found that the photoresponse observed after the injection of cGMP was dramatically reduced compared with the photoresponse before the injection. The initial depolarization was suppressed almost completely after a 3-min cGMP injection but then gradually recovered (Fig. 6a). This response is consistent with responses recorded previously in light-adapted Type B photoreceptors (32).


View larger version (15K):
[in this window]
[in a new window]
 
Fig. 6.   Effects of injected cGMP and extracellular Na+ and Ca2+ concentration on Hermissenda photoresponses. a, injection of cGMP reduced the photoresponse in cells maintained in normal ASW containing 10 mM Ca2+. b, the inhibitory effect of cGMP was abolished in low Ca2+ (1 mM) ASW. c, the cGMP-evoked response was unchanged in Na+-free ASW. d, inhibition of the cGMP-induced response in Ca2+-free ASW (10 mM CaCl2 was replaced with equimolar CdCl2). e, the photoresponse was reduced in Na+-free ASW. f, the photoresponse was unchanged in Ca2+-free ASW.

The effect of cGMP or phosphodiesterase inhibitors on the photoresponse has been reported to vary with the extracellular Ca2+ concentration (45). Consistent with previous reports (43), we also found that cumulative cGMP, by pretreatment with cGMP via iontophoretic injection, dramatically decreased the photoresponse of light-adapted photoreceptors maintained in normal ASW but enhanced the photoresponse of cells maintained in low Ca2+ ASW (1 mM; Fig. 6b). The inhibitory effect of cGMP recovered after returning to normal ASW (data not shown). The cGMP-induced response was found to be insensitive to changes in extracellular Na+ concentration (Fig. 6c), unlike native photoresponses (Fig. 6e). Moreover, the cGMP-induced response was abolished in Ca2+-free ASW (Fig. 6d), unlike native photoresponses, which were independent of extracellular Ca2+ (Fig. 6f).

    DISCUSSION
Top
Abstract
Introduction
Procedures
Results
Discussion
References

The results of the present study demonstrate for the first time that IP3 may mediate invertebrate visual transduction, particularly in Hermissenda. Although cAMP, cGMP, and Ca2+ have been proposed to activate several types of channels, injection of these second messenger candidates did not reproduce the native photoresponse. In contrast, injections of IP3 produced responses that were very similar to the native photoresponse, whereas Ca2+ acted as a modulator of the photoresponse (46).

The hypothesis that IP3 may be the second messenger involved in visual transduction in Hermissenda is supported by the results of the present study and by results obtained previously: 1) light flashes result in greater increases in intracellular IP3 than cyclic nucleotides (25) and 2) inhibition of PLC activity and reduction of phosphoinositide turnover result in a reduction in the amplitude of the native photoresponse (13). Although the primary role of IP3 has been considered to be the release of Ca2+ from intracellular stores, several IP3-gated ion channels have been recently characterized in olfactory cilia (37, 38) and rat megakaryocytes (39), raising the possibility that IP3 directly activates a transduction channel in Hermissenda.

The possibility that IP3 may be a second messenger in Drosophila visual transduction is supported by observations by Inoue et al. (10) that a reduction of PIP2-PLC activity is closely correlated with electrophysiological abnormality in the Drosophila phototransduction mutant norpA (no receptor potential A) eye. Furthermore, the norpA gene has been shown to encode PLC (11, 47). Yoshioka et al. (43) have also reported previously that IBMX inhibits phosphoinositide turnover and that the photoresponse is dependent on PIP2 hydrolysis by PLC in squid photoreceptor. The photoresponse in Limulus has also been shown to be diminished by the injection of the PLC inhibitor neomycin without affecting the response to IP3 (14) and by polyamine injection (17). Therefore, we propose that IP3 produced from PIP2 hydrolysis via PLC activation is an essential component of invertebrate visual transduction.

The question remains about whether IP3 acts directly or via Ca2+ in Hermissenda visual transduction. In the present study, injection of Ca2+ into the photoreceptor in Hermissenda induced no response in darkness, suggesting that Ca2+ is not directly involved. Furthermore, excitation occurs even in the absence of an IP3-induced increase in intracellular Ca2+ in Limulus (17) and in Drosophila mutants lacking IP3 receptors in photoreceptor cells (19). It has also been reported that the photoresponse precedes the rise of intracellular Ca2+ in Limulus (48, 49). Recently, Hardie (18) reported that a transient elevation of Ca2+ using a caged Ca2+ compound did not directly excite Drosophila photoreceptors. These results indicate that Ca2+ is unlikely to be directly involved in phototransduction in Drosophila, Hermissenda, and Limulus but may act as a modulator of the photoresponse.

Several previous studies indicate that Ca2+ excites photoreceptors (50-52) and that the injection of a Ca2+ buffer reduced the photoresponse in Limulus (50). Also, in the present study, reduction of intracellular Ca2+ by a Ca2+ chelator resulted in a reduction of the photoresponse; however, the mechanism underlying this response is presently unclear. It may be because of reduced activation of PLC and a subsequent decrease in IP3; however, a decrease in protein kinase C activity cannot be ruled out. According to Thio and Sontheimer (53), phorbol esters reduced the peak of the TTX-sensitive Na+ current by 25-60% and potentiated the TTX-resistant Na+ current by 60-150%. In the present study, the Ca2+-induced increase in the photoresponse was 60-80% of control, which is consistent with the phorbol ester-induced increase in the TTX-resistant Na+ current.

Involvement of cyclic nucleotides in visual transduction is also unlikely. The cAMP-evoked response was very different from the light-evoked response; injection of cAMP induced short bursts of Na+-dependent action potentials. Repeated injection evoked trains of similar bursts, indicating that these action potentials may be mediated by fast-inactivating cAMP-sensitive Na+ channels.

Interestingly, cGMP-evoked responses were similar to light-evoked responses, but the following differences were observed: the amplitude of the cGMP-evoked responses depended on the distance from the rhabdomeric membrane, but the latency of the response was constant for all trials; the rising phase of the responses to cGMP was faster than that of responses to light; the cGMP-evoked response depended on external Ca2+, whereas the light-evoked response depended on external Na+; and the response induced by long term cGMP injection and the light-evoked response from light-adapted cells were very similar. Taken together, these findings indicate that neither cAMP nor cGMP act as second messengers in invertebrate visual transduction. Thus the results of the present study suggest that the transduction channels of Drosophila and Hermissenda eye may be IP3-gated Na+ channels. Cloning of IP3-gated Na+ channels may help clarify the mechanisms underlying invertebrate visual transduction.

    FOOTNOTES

* This work was supported by Grant-in-Aid for Scientific Research on Priority Areas on "Functional Development of Neural Circuits" 07279105 from the Ministry of Education, Science, Sports, and Culture of Japan and also by Grant-in-Aid for the "Research for the Future Program" RFTF96L00310 from the Japanese Society for the Promotion of Science.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.

§ To whom correspondence should be addressed. Tel.: 81-559-68-1111, Ext. 4504; Fax: 81-559-68-1156; E-mail: sakaki{at}fb.u-tokai.ac.jp.

The abbreviations used are: IP3, inositol trisphosphatePIP2, phosphatidylinositol 4,5-bisphosphatePLC, phospholipase CBAPTA, bis(0-aminophenoxy) ethane-N,N,N',N'-tetraacetic acidASW, artificial sea waterIBMX, IsobutylmethylxanthineTTX, tetrodotoxin.
    REFERENCES
Top
Abstract
Introduction
Procedures
Results
Discussion
References

  1. Hardie, R. C. (1993) Nature 366, 113-114[Medline] [Order article via Infotrieve]
  2. Nagy, K. (1991) Q. Rev. Biophys. 24, 165-226[Medline] [Order article via Infotrieve]
  3. Pak, W. L., and Shortridge, R. D. (1991) Photochem. Photobiol. 53, 871-875
  4. Brown, J. E., Rubin, L. J., Ghalayni, A. J., Tarver, A. P., Irvine, R. F., Berridge, M. J., and Anderson, R. E. (1984) Nature 311, 160-163[Medline] [Order article via Infotrieve]
  5. Fein, A., Payne, R., Corson, D. W., Berridge, M. J., and Irvine, R. F. (1984) Nature 311, 157-160[Medline] [Order article via Infotrieve]
  6. Szuts, E. T., Woods, S. F., Reid, M. S., and Fein, A. (1986) Biochem. J. 240, 929-932[Medline] [Order article via Infotrieve]
  7. Brown, J. E., Watkins, D. C., and Malbon, C. C. (1987) Biochem. J. 247, 293-297[Medline] [Order article via Infotrieve]
  8. Wood, S. F., Szuts, E. Z., and Fein, A. (1989) J. Biol. Chem. 264, 12970-12976[Abstract/Free Full Text]
  9. Yoshioka, T., Inoue, H., and Hotta, Y. (1983) Biochem. Biophys. Res. Commun. 111, 567-573[Medline] [Order article via Infotrieve]
  10. Inoue, H., Yoshioka, T., and Hotta, Y. (1985) Biochem. Biophys. Res. Commun. 132, 513-519[Medline] [Order article via Infotrieve]
  11. Bloomquist, B. T., Shortridge, R. D., Schneuwly, S., Perdew, M., Montell, C., Steller, H., Rubin, G., and Pak, W. L. (1988) Cell 54, 723-733[Medline] [Order article via Infotrieve]
  12. McKay, R. R., Chen, D. M., Miller, K., Kim, S., Stark, W. S., and Shortridge, R. D. (1995) J. Biol. Chem. 270, 13271-13276[Abstract/Free Full Text]
  13. Sakakibara, M., Alkon, D. L., Kouchi, T., Inoue, H., and Yoshioka, T. (1994) Biochem. Biophys. Res. Commun. 202, 299-306[CrossRef][Medline] [Order article via Infotrieve]
  14. Frank, T. M., and Fein, A. (1991) J. Gen. Physiol. 97, 697-723[Abstract]
  15. Bolsover, S. R., and Brown, J. E. (1985) J. Physiol. (Lond.) 364, 381-393[Abstract]
  16. O'Day, P. M., and Gray-Keller, M. P. (1989) J. Gen. Physiol. 93, 473-492[Abstract]
  17. Faddis, M. N., and Brown, J. E. (1993) J. Gen. Physiol. 101, 909-931[Abstract]
  18. Hardie, R. C. (1995) J. Neurosci. 15, 889-902[Abstract]
  19. Acharya, J. K., Jalink, K., Hardy, R. W., Hartenstein, V., and Zucker, C. S. (1997) Neuron 18, 881-887[Medline] [Order article via Infotrieve]
  20. Johnson, E. C., Robinson, P. R., and Lisman, J. E. (1986) Nature 324, 468-470[Medline] [Order article via Infotrieve]
  21. Bacigalupo, J., Bautista, D. M., Brink, D. L., Hetzer, J. F., and O'Day, P. M. (1995) J. Neurosci. 15, 7196-7200[Abstract]
  22. Bacigalupo, J., Johnson, E. C., Vergara, C., and Lisman, J. E. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 7938-7942[Abstract]
  23. Brown, J. E., Kaupp, U. B., and Malbon, C. C. (1984) J. Physiol. (Lond.) 353, 523-539[Abstract]
  24. Saibil, H. R. (1984) FEBS Lett. 168, 213-216[CrossRef][Medline] [Order article via Infotrieve]
  25. Brown, J. E., Faddis, M., and Combs, A. (1992) Exp. Eye Res. 54, 403-410[Medline] [Order article via Infotrieve]
  26. Gomez, M. P., and Nasi, E. (1995) Neuron 15, 607-618[Medline] [Order article via Infotrieve]
  27. Dennis, M. (1967) J. Neurophysiol. 30, 1439-1465[Free Full Text]
  28. Alkon, D. L. (1973) J. Gen. Physiol. 61, 444-461[Abstract/Free Full Text]
  29. Alkon, D. L. (1976) J. Gen Physiol. 67, 197-211[Abstract]
  30. Alkon, D. L., and Fuortes, M. G. F. (1972) J. Gen. Physiol. 60, 631-649[Abstract/Free Full Text]
  31. Alkon, D. L., and Grossman, Y. (1978) J. Neurophysiol. 41, 1328-1342[Free Full Text]
  32. Detweiler, P. B. (1976) J. Physiol. 256, 691-708[Medline] [Order article via Infotrieve]
  33. Grossman, Y., Schmidt, J. A., and Alkon, D. L. (1981) Comp. Biochem. Physiol. 68A, 487-494
  34. Takeda, T. (1982) Vision Res. 22, 303-309[Medline] [Order article via Infotrieve]
  35. Etcheberrigaray, R., Huddie, P. L., and Alkon, D. L. (1991) J. Exp. Biol. 156, 619-623[Medline] [Order article via Infotrieve]
  36. Alkon, D. L., and Sakakibara, M. (1985) Biophys. J. 48, 983-995[Abstract]
  37. Hatt, H., and Ache, B. W. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 6264-6268[Abstract]
  38. Honda, E., Teeter, J. H., and Restrepo, D. (1995) Brain Res. 703, 79-85[CrossRef][Medline] [Order article via Infotrieve]
  39. Somasundaram, B., and Mahaut-Smith, M. P. (1995) J. Biol. Chem. 270, 16638-16644[Abstract/Free Full Text]
  40. Payne, R., and Fein, A. (1986) J. Gen. Physiol. 87, 243-269[Abstract]
  41. Weckstrom, M., Kouvalainen, E., and Jarvilehto, M. (1988) Acta Physiol. Scand. 132, 103-113[Medline] [Order article via Infotrieve]
  42. Nomura, K., Naruse, K., Watanabe, K., and Sokabe, M. (1990) J. Membr. Biol. 115, 241-251[Medline] [Order article via Infotrieve]
  43. Yoshioka, T., Inoue, H., Takagi, M., Hayashi, F., and Amakawa, T. (1983) Biochim. Biophys. Acta 755, 50-55[Medline] [Order article via Infotrieve]
  44. Feng, J. J., Frank, T. M., and Fein, A. (1991) Brain Res. 552, 291-294[Medline] [Order article via Infotrieve]
  45. Johnson, E. C., and O'Day, P. M. (1995) J. Neurosci. 15, 6586-6591[Medline] [Order article via Infotrieve]
  46. Levy, S., and Fein, A. J. (1985) J. Gen. Physiol. 85, 805-841[Abstract]
  47. Toyoshima, S., Matsumoto, N., Wang, P., Inoue, H., Yoshioka, T., Hotta, Y., and Osawa, T. (1990) J. Biol. Chem. 265, 14842-14848[Abstract/Free Full Text]
  48. Steive, H., and Benner, S. (1992) Vision Res. 32, 403-416[Medline] [Order article via Infotrieve]
  49. Ukhanov, K. Y., Flores, T. M., Hsiao, H. S., Mohapatra, P., Pitts, C. H., and Payne, R. (1995) J. Gen. Physiol. 105, 95-116[Abstract]
  50. Payne, R., Corson, D. W., and Fein, A. J. (1986) J. Gen. Physiol. 88, 107-126[Abstract]
  51. Payne, R., Corson, D. W., Fein, A. J., and Berridge, M. J. (1986) J. Gen Physiol. 88, 127-142[Abstract]
  52. Shin, J., Richard, E. A., and Lisman, J. (1993) Neuron 11, 845-855[Medline] [Order article via Infotrieve]
  53. Thio, C. L., and Sontheimer, H. (1993) J. Neurosci. 13, 4889-4897[Abstract]


Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.