The excitation cascade of Limulus ventral photoreceptors: guanylate cyclase as the link between InsP3-mediated Ca2+release and the opening of cGMP-gated channels
© Garger et al; licensee BioMed Central Ltd. 2004
Received: 19 November 2003
Accepted: 26 February 2004
Published: 26 February 2004
Early stages in the excitation cascade of Limulus photoreceptors are mediated by activation of Gq by rhodopsin, generation of inositol-1,4,5-trisphosphate by phospholipase-C and the release of Ca2+. At the end of the cascade, cGMP-gated channels open and generate the depolarizing receptor potential. A major unresolved issue is the intermediate process by which Ca2+ elevation leads to channel opening.
To explore the role of guanylate cyclase (GC) as a potential intermediate, we used the GC inhibitor guanosine 5'-tetraphosphate (GtetP). Its specificity in vivo was supported by its ability to reduce the depolarization produced by the phosphodiesterase inhibitor IBMX. To determine if GC acts subsequent to InsP3 production in the cascade, we examined the effect of intracellular injection of GtetP on the excitation caused by InsP3 injection. This form of excitation and the response to light were both greatly reduced by GtetP, and they recovered in parallel. Similarly, GtetP reduced the excitation caused by intracellular injection of Ca2+. In contrast, this GC inhibitor did not affect the excitation produced by injection of a cGMP analog.
We conclude that GC is downstream of InsP3-induced Ca2+ release and is the final enzymatic step of the excitation cascade. This is the first invertebrate rhabdomeric photoreceptor for which transduction can be traced from rhodopsin photoisomerization to ion channel opening.
Phototransduction processes in invertebrates have both similarities and differences from that in vertebrate rods. The initial enzymatic step in all photoreceptors is the activation of G protein by rhodopsin. In the ciliary photoreceptors of vertebrate rods and cones, G protein activates phosphodiesterase leading to a decrease of cGMP concentration, closure of cyclic nucleotide-gated channels and membrane hyperpolarization (for review see ). On the other hand, the ciliary photoreceptors from scallops, hyperpolarize due to an increase in cGMP which opens a K+ selective conductance . In invertebrate rhabdomeric photoreceptors, which also depolarize in response to light, no complete transduction cascade has been determined. It is clear that G protein activates phospholipase C in all cases examined so far, including Drosophila [3–5], Limulus [6, 7] and squid [8, 9]. PLC then hydrolyzes phosphatidylinositol-4,5-bisphosphate to produce inositol-1,4,5-trisphosphate and diacylglycerol.
Subsequent steps differ among these photoreceptors. In late stages of the excitation cascade in Drosophila, diacylglycerol (or metabolites) may lead to channel opening [10, 11]. However, understanding the final stages has been hampered by the unavailability of a direct assay for the light-dependent channels and varying results using heterologous expression systems . In the photoreceptors of Limulus ventral eye (for review see ), the cascade involves PLC, InsP3, Ca2+ and cGMP. Light produces an InsP3-induced Ca2+ elevation that precedes the onset of the receptor potential . Furthermore, intracellular injection of Ca2+ mimics the light response [15–17] and buffering intracellular Ca2+ inhibits it [16, 18]. Taken together, these results establish that InsP3-mediated Ca2+ elevation is an integral part of the excitation cascade. The Limulus cascade ends with the opening of cGMP-gated channels which, in this system, can be directly studied in cell-attached and excised patches [19, 20]. Photoreceptor cells contain mRNA for a putative Limulus cyclic nucleotide-gated channel protein, and antibodies to the expressed protein specifically label the light-sensitive rhabdomeric lobe [21, 22]. Furthermore either intracellular injection of cGMP [23, 24] or elevation of cGMP by inhibition of phosphodiesterase [25, 26] excites the cell. There is thus little doubt that the end of the cascade involves cGMP-gated channels. What remains unclear is the mechanism that couples Ca2+ release to cGMP elevation.
Recent work demonstrated that inhibitors of guanylate cyclase strongly reduce the response to light . Although these results support the requirement for cGMP during excitation, they do not indicate at which stage GC is involved. In this paper, we test the hypothesis that GC is a missing link in the cascade; i.e. that it acts downstream from Ca2+ elevation as required if cGMP is to couple Ca2+ elevation to channel opening. Our results indicate that this is indeed the case. Because PDE inactivation is unlikely to be involved in excitation (see Discussion), it appears that activation of GC is what elevates cGMP. It is therefore now possible to a give a rather complete picture of this complex cascade that couples rhodopsin photoisomerization to ion channel opening.
Guanylate cyclase antagonists oppose the effects of PDE inhibitors
GC inhibitors act downstream from InsP3 mediated Ca2+release
In order to provide a link between light-induced Ca2+ elevation and the opening of cGMP-dependent channels, GC activity must be downstream from Ca2+ in the signaling cascade. To determine if this is the case, photoreceptors were excited by injecting InsP3 or Ca2+ directly into the light-transducing lobe (the R-lobe) [6, 7, 15–17]. If GC is downstream, this form of excitation should be reduced by GC inhibitors. A similar strategy has been used previously to characterize the ordering of other steps in the cascade [15, 18, 28, 29].
GC inhibitors act prior to the opening of cyclic nucleotide gated channels
There has been substantial previous work on the phototransduction cascade in Limulus, but the reactions involved in the late stages of the process have been unclear. In particular, there has been no information on enzymatic steps downstream from InsP3-mediated Ca2+ elevation that might couple this elevation to channel opening. Recently, it was shown that GC was required in the cascade , but its position in the cascade was not known. Here we have demonstrated that GC is downstream from Ca2+ and thus situated appropriately to mediate late stages of the cascade. As a result, a rather complete picture of the transduction cascade is now possible. In the paragraphs below, we provide an overview of this cascade and delineate areas where gaps remain.
InsP3 produces a Ca2+ efflux from intracellular stores and can raise cytosolic Ca2+ upwards of 150 μ M [6, 7, 44, 45]. Excitation by light or InsP3 is blocked by the InsP3 receptor antagonist heparin [18, 29]. Direct measurements show that Ca2+ release is sufficiently fast to activate the light-dependent conductance [14, 45]. The InsP3 receptor is localized in the endoplasmic reticulum adjacent to the base of the rhodopsin-containing microvilli at the site of Ca2+ release . Excitation can be mimicked by raising intracellular Ca2+ [15–17] and thwarted by Ca2+ buffers [16, 18]. Ca2+ elevation is thus necessary and sufficient for excitation.
Several lines of work indicate that the final step is the activation of cGMP-gated channels. Excitation can be induced by PDE inhibitors [25, 47] or by intracellular injection of cGMP [23, 24]. Most importantly, cGMP can directly activate channels when applied to inside-out excised membrane patches from the R-lobe . These channels have properties similar to the light-activated channels in cell-attached patches on the R-lobe . Most recently, a putative cyclic nucleotide-gated channel gene has been cloned from Limulus . The mRNA for the channel is expressed in photoreceptors and the protein product was specifically localized in the R-lobe .
The work reported here shows that GC is appropriately positioned in the cascade to couple the light-induced Ca2+ elevation to the production of cGMP. In principle, the role of GC could be simply to constitutively produce cGMP; during light cGMP might be elevated due to a decrease in PDE activity. However, such a decrease in PDE activity during light exposure would probably enhance the response to injected cGMP relative to the dark-adapted response and certainly not decrease it, the observed effect . These results thus strongly suggest that the GC is activated as a result of the light-induced elevation of Ca2+. Because there are few photoreceptors in the ventral eye, this preparation is not well-suited for biochemistry to the extent that experiments to test for the Ca2+ or light-dependence of GC are not practical. Therefore what is known in these photoreceptors about GC is based on its pharmacological profile. It has been concluded that the GC involved is not the soluble, NO-dependent form and therefore does not rely on Ca2+-dependent activation of nitric oxide synthase . An important unresolved issue is how the enzyme might be regulated by Ca2+. Several precedents for Ca2+-dependent activation of this enzyme must be considered. For instance, in vertebrates Ca2+-dependent GC activating proteins (CD-GCAPs) and neurocalcin are known to activate rod GC [49, 50]. The concentration of Ca2+ required for this activity is well within the range achieved during Limulus phototransduction [44, 45]. In ciliates there is a form of GC that can be activated by Ca2+/calmodulin . This raises the question of whether GC activation in Limulus might be mediated by calmodulin. The involvement of calmodulin in a critical step in the transduction cascade could be one reason for the high concentrations of calmodulin found in Limulus R-lobes .
The Limulus cascade is more complex than that of the vertebrate rod, but this increased complexity can be viewed in light of the remarkable performance characteristics of Limulus photoreceptors. These cells generate single photon responses in the nA range, three orders of magnitude larger than those of the rod. Furthermore, Limulus photoreceptors respond over nearly 4 orders of magnitude greater range of light intensities than rods [53, 54]. The Limulus cascade has eight stages compared to the five stages of the rod cascade. The larger number of stages may underlie the greater single-photon response and wider dynamic range seen in Limulus photoreceptors.
Although much has been determined about the phototransduction cascade in Limulus, the late steps occurring between InsP3-induced Ca2+ elevation and the opening of the cGMP-gated channels has been unclear. Previous work showed that guanylate cyclase was necessary for generation of the light-response, but did not identify where in the cascade it acted . The major question answered in the present study is to determine whether GC is appropriately positioned at the end of the cascade where it could couple Ca2+ elevation to cGMP elevation. Our conclusion is that this is the case; the excitation produced by either InsP3 or Ca2+ injection can be greatly reduced by inhibiting GC (Figs. 2, 3). Importantly the GC inhibitor did not affect the excitation produced by injection of cGMP analog (Fig. 4); therefore channel function appears unaffected. Taken together with previous results, a picture of the enzymatic steps by which rhodopsin is coupled to channel activation in an invertebrate rhabdomeric photoreceptor can now be proposed (Fig. 5).
The simplest interpretation of the available data is that GC activation is the primary means by which the intracellular concentration of cGMP is increased during excitation in Limulus photoreceptors. This hypothesis can be tested by characterizing the specific guanylate cylase involved and the link between Ca2+ release and cyclase activation.
The dissection and techniques for electrophysiology have been described in detail elsewhere . Cells were exposed to stimulus light with a maximal light intensity of 1.0 mW/cm2 which was attenuated by neutral density filters (attenuation = 10ND). Cells were perfused with artificial sea water (ASW) with the composition (in mM) 425 NaCl, 10 KCl, 10 CaCl2, 22 MgCl2, 26 MgSO4, and 15 Tris, adjusted to pH 7.8. Non-injecting intracellular microelectrodes contained 3 M KCl (15–25 mΩ resistance). Injection microelectrodes contained drugs as described in the text with (in mM) 150 KCl, 10 HEPES, 0.001% Triton X-100  and had 7–15 mΩ resistance. The microelectrodes used to inject Ca2+ contained 1.8 mM Ca2+ buffered with HEDTA. This use of HEDTA has been described elsewhere and shown to not affect excitation or light adaptation . GtetP, HEDTA, and IBMX were obtained from Sigma; InsP3 and 3dInsP3 from Calbiochem; Rp-8pCPT-cGMPS from Biolog.
The selection and observation of cells has been described in detail elsewhere . Briefly, cells were observed under infrared illumination with Hofmann optics using a Cooke Corporation Sensicam. Cells were chosen on the basis of having a stable membrane potential and robust dark adapted and single photon light responses.
In some experiments the electrodes had to be placed into the light-sensitive R lobe of the cells. Under Hoffman optics, the R-lobe has a smooth appearance, contrasted with the granular appearance of the light-insensitive A-lobe. In these cases, the tip of the electrode was positioned at the border of the two lobes and advanced axially into the R-lobe.
Intracellular pressure injection
Injection electrodes were backfilled with at least 2 μL of solution and routinely recorded membrane potentials approximately 20 mV higher than 3 M KCl electrodes. Injections were observed on a monitor. The pulse duration and pressure were adjusted to maintain a constant bolus size. Injection electrodes became clogged on occasion, and the blockage was cleared using either a manually controlled high pressure pulse or brief (< 30 ms) oscillation train. If the cell's light or drug injection responses were affected by the clearing procedure, that experiment was not used.
Rp-8-(4-chlorophenylthio)guanosine-3' 5'-cyclic monophosphorothioate
This grant was supported by NIH EYO1496 and support from the W. M. Keck Foundation.
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