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Calcium Channels Formed by Mammalian Trp Homologues

Xi Zhu and Lutz Birnbaumer

X. Zhu is Assistant Professor of the Dept. of Pharmacology and the Neurobiotechnology Center, Ohio State Univ., Columbus, OH 43210, USA; L. Birnbaumer is Professor and Chairman of the Dept. of Molecular, Cell, and Developmental Biology, Univ. of California at Los Angeles, Los Angeles, CA 90095, USA.

	Abstract

 
Homologues of Drosophila trp genes have been isolated from mammalian species in hope that they may constitute the molecular basis of capacitative Ca²⁺ entry. Expression of Trps suggests that they form Ca²⁺ influx channels regulated by either store depletion or a more upstream event. Store-operated Trp channels can be formed by heteromultimerization.

	Introduction

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
The past three years have been exciting for those who study Ca²⁺ signaling in nonexcitable cells. This is largely because genes coding for homologues of the Drosophila melanogaster Trp channels were finally identified and isolated from mammalian species. The name trp came from a spontaneous mutation called transient receptor potential, which affects the fly's vision so that the electroretinogram of the mutant eyes lacks the sustained activity. The genetic defect in this mutant leads to the absence of a photoreceptor-specific plasma membrane Ca²⁺ entry channel (6). Trp-related proteins have long been speculated to form capacitative Ca²⁺ entry (CCE) channels. CCE is ubiquitously present in both nonexcitable and excitable cells. It is an important process in Ca²⁺ signaling activated as a result of receptor-regulated stimulation of phospholipase C (PLC).

	CCE is a necessary component of the PLC-mediated Ca2+ signaling cascade

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
Cytosolic Ca²⁺ is tightly controlled, and changes in intracellular Ca²⁺ concentration ([Ca²⁺]_i) affect a large array of cellular processes. Ca²⁺ often serves as an intracellular mediator for extracellular signals. At rest, cells maintain a low [Ca²⁺]_i of ~10^–7 M. Increases from this level in both magnitude and duration and the frequency with which they occur can trigger various kinds of Ca²⁺-regulated intracellular events, allowing cells to respond properly to extracellular stimuli. Cells store Ca²⁺ in the endoplasmic reticulum (ER). This provides one Ca²⁺ source for [Ca²⁺]_i to increase. Another Ca²⁺ source is the extracellular space, where Ca²⁺ concentration is at 10^–3 M. A quick way to increase [Ca²⁺]_i is to allow Ca²⁺ to flow into the cytosol from these sources by opening Ca²⁺ channels located on either the ER or the plasma membrane. In the case of PLC-mediated signaling, both Ca²⁺ sources are used to produce a distinct pattern of [Ca²⁺]_i changes.

Activation of PLC is a common route for the action of many hormones, neurotransmitters, and growth factors. The ß-type PLC is activated by members of the _q-family and ß-subunits of heterotrimeric G proteins following receptor activation, whereas the -type PLC is activated by receptor tyrosine kinases. As illustrated in Fig. 1, PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate and produces 1,2-diacylglycerol and inositol 1,4,5-trisphosphate (IP₃). IP₃ is the natural ligand for a set of Ca²⁺ channels located on the ER membrane, the IP₃ receptors. IP₃ binding leads to the opening of the IP₃ receptor and release of Ca²⁺ from its internal stores into the cytosol. This forms the first phase of the PLC-mediated Ca²⁺ signaling process, which is often referred to as Ca²⁺ mobilization. Figure 2 shows how the process is observed experimentally. Human embryonic kidney (HEK) 293 cells were grown on glass coverslips and were loaded with fura 2, a fluorescent Ca²⁺ indicator dye. [Ca²⁺]_i in individual cells was measured by Ca²⁺ imaging using an inverted microscope attached to a xenon light source that provides alternating excitation light at 340 and 380 nm. The ratio of fura 2 fluorescence captured by an intensified charge-coupled device camera under these two excitation conditions correlates with [Ca²⁺]_i. In Fig. 2, left, cells were incubated in a physiological solution containing 1.8 mM Ca²⁺. Addition of an agonist (100 µM carbachol) to the medium caused a rapid increase of [Ca²⁺]_i. The increase was transient, and [Ca²⁺]_i quickly decreased to a level that is still substantially higher than the resting [Ca²⁺]_i. This is the second, or sustained, phase of Ca²⁺ increase following stimulation of PLC. It is worth pointing out that the [Ca²⁺]_i level during the sustained phase varies largely from one cell type to another, in part due to the differences in the activity of Ca²⁺-adenosine 5'-triphosphatases (ATPases) (Ca²⁺ pumps). It is generally accepted that the active extrusion of Ca²⁺ from cytosol to ER and external space by the Ca²⁺ pumps is the major cause of the rapid decrease of [Ca²⁺]_i. If left unchecked, the pumps would eventually eliminate all cellular Ca²⁺ if no external Ca²⁺ was available for replenishment via an influx pathway. This is indeed true. As shown in Fig. 2, right, if cells were incubated in a medium containing no free Ca²⁺, agonist-stimulated [Ca²⁺]_i increase would still occur. However, it would, in general, have a lower peak level than when external Ca²⁺ was present and would decrease to the basal level within a few minutes. Readdition of Ca²⁺ to the extracellular medium of these cells would cause [Ca²⁺]_i to increase again (shaded area in Fig. 2). Therefore, external Ca²⁺ contributes to the sustained phase of [Ca²⁺]_i increase by its influx through plasma membrane Ca²⁺ entry channels. Inevitably, Ca²⁺ influx is associated with PLC-mediated Ca²⁺ signaling under physiological conditions. By refilling the internal stores, Ca²⁺ influx serves as a crucial process for cells to respond to the continued presence of extracellular stimuli.

View larger version (30K): [in this window] [in a new window]   FIGURE 1. Diagram of stimulation of phospholipase C (PLC) and activation of Ca2+ signaling cascade. For simplicity, activation of PLC- by receptor tyrosine kinases is not shown. PLC-ß can be activated by either the -subunit of the Gq family or ß-subunits dissociated from the Gi family of G proteins. Two sources contribute to the intracellular Ca2+ concentration ([Ca2+]i) increase. On inositol 1,4,5-trisphosphate (IP3) binding, Ca2+ in the internal store is released via an intracellular Ca2+ release channel, the IP3 receptor (IP3R). Ca2+ also comes in from extracellular space via undefined Ca2+ influx channels. Influx channel is activated by an undefined store depletion signal. Ca2+ pumps located on the endoplasmic reticulum (ER) [sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA)] and plasma membrane [plasma membrane Ca2+-ATPase (PMCA)] actively remove Ca2+ from cytosol into the ER or external space. PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, 1,2-diacylglycerol.

View larger version (17K): [in this window] [in a new window]   FIGURE 2. Examples of intracellular Ca2+ concentration ([Ca2+]i) changes in agonist-stimulated cells. Fura 2-loaded human embryonic kidney 293 cells were studied by Ca2+ imaging as described in the text. Traces show [Ca2+]i changes in individual cells; 100 µM carbachol was added at 1 min (arrows). Left: cell was kept in medium containing 1.8 mM Ca2+. Right: cell was kept in medium containing no free Ca2+. After stimulation by carbachol, 1.8 mM Ca2+ was added to the medium at 4 min. Shaded areas show a simplified view of the component of [Ca2+]i changes that is dependent on Ca2+ influx.

	Drosophila phototransduction process is PLC mediated, and Trp is a SOC

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
Major efforts have been made to molecularly identify the CCE channels, whether they are store operated or otherwise. However, the ubiquitous nature of CCE and the lack of a specific inhibitor for CCE have made expression cloning or purification a difficult task. Therefore, much attention was given to the identification of homologues of the only known gene thought to be related to CCE, the Drosophila trp gene.

Phototransduction in insects is mediated by a G protein and a PLC. Studies of a Drosophila vision mutant showed that responses to light are completely blocked by a null mutation of the norpA gene that encodes a PLC-ß isoform. Thus the activation of PLC-ß is linked to the opening of an ion channel and membrane depolarization, which gives rise to the receptor potential that persists for as long as the receptor cell is illuminated. The sustained light-activated conductance is highly permeable to Ca²⁺, but, in the trp mutant, the Ca²⁺ permeability is greatly reduced (6). Although the initial cloning of the trp gene revealed that it is a membrane-associated protein with no close relatives, a related Drosophila protein, isolated as a calmodulin-binding protein, was subsequently characterized and named Trp-like (Trpl) because of its similarity to Trp. Both Trp and Trpl are photoreceptor specific and have predicted structural features similar to that of a single domain of voltage-gated ion channels; namely, they appear to have six transmembrane segments and cytosolically localized amino and carboxy termini. Of particular interest was that the last four putative transmembrane segments (S3–S6) of Trp and Trpl are somewhat similar to those of the voltage-gated Na⁺ and Ca²⁺ channels, with the exception that only one lysine is present in the S4 segment of the Trp proteins. For the voltage-gated channels, four to six positively charged amino acid residues are present in the S4 segment, which constitutes the voltage sensor that promotes channel opening in response to changes in membrane potential. Thus it was suggested that Trp and Trpl are voltage-independent channels that are regulated by events following the light-activated PLC pathway in Drosophila photoreceptors (6).

The similarity between the mammalian PLC pathway and the insect's phototransduction process suggests that Trp and Trpl could form CCE channels. Indeed, recombinant Trp has been expressed in insect Sf9 cells, Xenopus laevis oocytes, and HEK 293T cells and shown to cause increases in inward current in response to treatment with IP₃ or TG (5, 10, 11). On the other hand, expression of Trpl in these cells led to the formation of a constitutively active nonselective cation channel. Stimulation by an agonist but not TG can further increase the activity of the Trpl channel.

	Trp homologues are present throughout the animal phylogeny

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
It is clear that Trp channels are involved in Ca²⁺ influx associated with PLC-mediated Ca²⁺ signaling. However, both proteins are strictly expressed in insect photoreceptor cells. The properties of channels formed by recombinant Trp and Trpl are also quite different from those of the CRAC channel or any other endogenous Ca²⁺ influx channel recorded from mammalian or insect cells (11). It was thus believed that a related channel must exist for Ca²⁺ influx that is activated by more generic types of G_q-coupled receptors and that is expressed more ubiquitously in Drosophila. Moreover, the CCE channels in mammalian cells may also be formed by a Trp-related protein. Although the pursuit for the third Drosophila trp gene has not been fruitful, the search for a mammalian homologue turned out to be surprisingly successful. This is due very significantly in part to the effort made by the human genome project and the availability of the dbEST (expressed sequence tag) database. The database, serving its proposed purpose to aid in the discovery of new human genes, contains several partial cDNA sequences that encode peptides with homology to the sequences of the Drosophila Trps. Three human genes (htrp1, htrp2, and htrp3) were identified on the basis of the dbEST sequences. Additional mouse (m), rat (r), and bovine (b) trp genes were identified using the classical reverse transcription coupled to polymerase chain reaction approach. Table 1 shows a current list of identified Trp homologues. The evolutionary distances of the Trp proteins are shown in Fig. 3. In mouse and quite possibly in other mammalian species, there are at least six trp genes. These genes can be divided into four major subtypes, with trp3 and trp6 belonging to one and trp4 and trp5 belonging to another.

View larger version (21K): [in this window] [in a new window]   FIGURE 3. Evolutionary relationships of members of Trp family. Phylogenetic analysis was performed using amino acid sequences from the putative transmembrane regions of Trps, which contain from 313 to 373 residues. Pairwise distances were calculated by Kimura protein distance analysis, and phylogram was generated by the UPGMA algorithm (GCG Wisconsin Sequence Analysis Package). GenBank accession numbers are shown in parentheses. *Unpublished sequences. **Sequence published by Monk et al., J. Neurochem. 67: 2227–2235, 1996. See Table 1 for explanation of abbreviations.

	Mammalian Trp proteins are involved in CCE

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
Mammalian Trp homologues have been expressed in cultured cells and found to form Ca²⁺ influx channels that are activated by a treatment with receptor agonists IP₃ or TG. In one set of experiments, the cDNA of hTrp1, hTrp3, or mTrp6 was transfected together with the cDNA of the M₅ muscarinic receptor into COSM6 cells. [Ca²⁺]_i was measured using the protocols shown in Fig. 2. The PLC pathway was activated by carbachol. The transfected cells responded to carbachol and showed a rapid increase in [Ca²⁺]_i. Between cells transfected with a trp and a control plasmid, there was no obvious difference in [Ca²⁺]_i changes due to Ca²⁺ mobilization. However, the extracellular Ca²⁺-dependent changes in [Ca²⁺]_i, which are reflective of CCE activity, were significantly altered in trp-transfected cells. Thus, when Ca²⁺ was present in the extracellular medium (as in Fig. 2, left), [Ca²⁺]_i decayed at a slower rate and reached a higher level in trp3- and trp6-transfected cells than in control cells. In Trp cells stimulated in the absence of extracellular Ca²⁺, readdition of Ca²⁺ (as in Fig. 2, right ) caused a faster increase of [Ca²⁺]_i, which also reached a higher level than in control cells. This was shown for cells transfected with htrp1, htrp3, or mtrp6. For hTrp1, the increase in [Ca²⁺]_i was less than that for hTrp3 and mTrp6 (2, 13). In patch-clamp experiments, injection of cDNA of hTrp1 in Chinese hamster ovary (CHO) cells led to the formation of a nonselective cation channel, which is activated by intracellular perfusion with IP₃ or treatment with TG (15). Transient transfection of the bovine trp4 in HEK 293 cells resulted in the formation of a SOC opened by either IP₃ or TG treatment (7). The Trp4 channel seems to be selective for divalent (Ba²⁺ and Ca²⁺) over monovalent (Na⁺ and Cs⁺) cations. More convincing evidence that mammalian Trps are involved in CCE was obtained when mouse fibroblast L cells were transfected with cDNA of mouse trps in the antisense direction. This resulted in a block of the endogenous L cell CCE activated by stimulation of the cotransfected M₅ receptor (13). Thus not only can the mammalian Trps form Ca²⁺ influx channels, but they also are directly or indirectly involved in the formation of the CCE channel.

However, there is a clear difference among Trp proteins concerning the mechanism of activation, similar to the difference found between DmTrp and DmTrpl. Although it has been clearly shown or stated that bTrp4 and hTrp1 are opened by store depletion caused by TG treatment, no convincing evidence has thus far been obtained to show that Trp3 or Trp6 are store operated. In fact, experimental results tend to indicate that they are not stimulated by store depletion. In COSM6 cells transfected with hTrp3, the TG-stimulated increase in Ca²⁺ influx is much smaller than that stimulated by carbachol (13). In cells transfected with mTrp6, no significant increase in Ca²⁺ influx can be observed when stimulated by TG (2). In both cases, addition of carbachol to the cells previously treated by TG causes additional Ca²⁺ influx, a phenomenon not seen in control cells. Therefore, it seems that the activation of Trp3 and Trp6 is dependent on the activation of receptors. A more recent report shows that Trp3 is not sensitive to store depletion but rather to Ca²⁺. However, the exact activation mechanism for Trp3 still remains unclear (14). In a recent study, we found that Ca²⁺ influx mediated by Trp3 is blocked by a PLC inhibitor, U-73122, suggesting that activation of PLC or production of IP₃ is required for Trp3 activation (12). On the other hand, both Trp3 and Trp6 tend to be spontaneously active when expressed in HEK 293 cells or CHO cells (12, 14). Electrophysiological studies also show that Trp3 and Trp6 form nonselective cation channels with relatively large single-channel conductance (60 pS for Trp3). These features are similar to that of DmTrpl and different from those expected for store-operated CCE channels.

It appears that store-operated activation is anything but the common feature for members of the Trp family, and it may be used as a way to classify the Trp proteins. Thus DmTrp, Trp1, and Trp4 appear to be store sensitive, whereas DmTrpl, Trp3, and Trp6 do not seem to respond to mere store depletion. For DmTrpl, the activator for channel opening may be IP₃ or the activated -subunit of a G protein, G₁₁ or G_q (see discussion in Ref. 12). In any case, the store depletion-insensitive influx channels are activated by a component of the PLC cascade and therefore are of physiological significance for the regulation of Ca²⁺ influx. Consistent with this idea, plasma membrane channels of unknown molecular structure activated by IP₃, inositol 1,3,4,5-tetrakisphosphate, G protein, or Ca²⁺ have been documented in various cell types (see review in Ref. 4 for details). It is clear that Trp channels play a role in Ca²⁺ influx following receptor activation by hormones, neurotransmitters, or growth factors that stimulate PLC.

	All Trps can form SOCs via multimerization, and proteins involved in Ca2+ signaling may be linked in a supramolecular complex

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 
We are still steps away from demonstrating that Trp channels are the same CCE channels from which the CCE model was developed over the years. Native CCE channels include the CRAC channel reported for mast cells, T lymphocytes, and endothelial and many other cells. They also include a relatively high-conductance SOC reported for A-431 epithelial cells, which conducts Ba²⁺ better than Ca²⁺ (4). A channel is evaluated by its properties, including the ion selectivity, sensitivity to blockers, unitary conductance, and tendency of rectification under negative or positive potentials. Because of insufficient electrophysiological data for the mammalian Trps, it is not yet possible to conclude whether the high-conductance SOC is a type of Trp channel, for example Trp1 or Trp4. However, it is clear that in no case has the current developed due to a heterologous expression of a Trp that mimicked the properties of I_CRAC, which is quite unique with very high Ca²⁺ selectivity and very small unitary conductance (<1 pS).

One possibility is that the CRAC channel is formed by a yet unknown protein, which may or may not be Trp related. Another possibility is that a native channel is a heteromultimer composed of several Trps plus some other auxiliary subunits (1). Multimerization of Trps has recently been shown for DmTrp and DmTrpl. Coexpression of DmTrp and DmTrpl in Xenopus oocytes leads to the appearance of a channel with an ion selectivity and La³⁺ sensitivity different from those seen in oocytes expressing either protein alone (5). Interestingly, the new channel is activated to the same extent either by IP₃ or by TG, despite the fact that DmTrpl is a store-insensitive channel by itself. It has been shown biochemically that the amino termini of DmTrp and DmTrpl interact with each other (11). Coexpression of the two proteins in 293T cells gave rise to a SOC that had features from both DmTrp and DmTrpl. Moreover, coexpressing with DmTrp also prevented the basal inward current seen when DmTrpl was expressed alone. Thus it was proposed that DmTrpl in photoreceptors may only form heteromultimers with DmTrp or other Trp-related proteins so that its spontaneous activity is prevented. The same idea would apply to Trp3 and Trp6, which are functionally similar to DmTrpl. Because the DmTrp-DmTrpl complex is store depletion sensitive, one would expect that all Trps can take part in forming store-operated heteromultimeric channels as long as one subunit is capable of detecting the store depletion signal. This provides a possibility that multiple channels formed by Trps in various combinations act in concert through multiple regulatory pathways in a cell-specific manner. Given the growing number of Trp homologues cloned and their tendency to form heteromultimeric channels, the potential that channels with distinct behavior exist is enormous. It is possible that one of these combinations constitutes the CRAC channel.

On the basis of the fact that the last four putative transmembrane segments of a Trp are similar to those of a single domain of voltage-gated Ca²⁺ and Na⁺ channels, a Trp-based channel may be a tetramer formed by four subunits (1). Like the voltage-gated ion channels, other auxiliary subunits may also be needed to form a native Ca²⁺ influx channel. Therefore, reconstitution of native channels from cloned trp genes remains a challenging task.

Recent studies on the Drosophila phototransduction molecules also revealed that DmTrp is physically linked to the upstream signaling proteins via direct association with a protein called InaD (3). InaD contains five PDZ domains, a protein interaction motif. The major rhodopsin, the PLC (NorpA), an eye-specific protein kinase C (InaC), and calmodulin are all associated with InaD. Thus the phototransduction molecules are all linked in a supramolecular complex. It remains unanswered whether proteins involved in the mammalian PLC cascade also exist as supramolecular complexes. A human InaD homologue was recently found in the dbEST database and cloned (8). It is twice as long as the Drosophila InaD (1,525 vs. 675 amino acids). Direct association of the human InaD with a Trp and other PLC-signaling proteins remains to be demonstrated.

In conclusion, the cloning of Trp homologues has opened a new era for elucidating the molecular basis of Ca²⁺ influx associated with stimulation of PLC and the consequent production of IP₃ and Ca²⁺ mobilization from its internal stores. For the most widely accepted CCE mechanism, the two major missing links are the nature of the store depletion signal and the structure of the plasma membrane channels. With the demonstration that some mammalian Trps are sensitive to store depletion and the possibility that store depletion-insensitive Trps may form store depletion-sensitive CCE channels via multimerization with a store-sensitive subunit, the molecular structure of CCE channels may have become apparent. Demonstration of the subunit structure of a CCE channel would aid in the identification of the store-depletion signal, since the channel is the target of such a signal.

	References

Top Introduction CCE is a necessary... Drosophila phototransduction... Trp homologues are present... Mammalian Trp proteins are... All Trps can form... References

 

1. Birnbaumer, L., X. Zhu, M. Jiang, G. Boulay, M. Peyton, B. Vannier, D. Brown, D. Platano, H. Sadeghi, E. Stefani, and M. Birnbaumer. On the molecular basis and regulation of cellular capacitative calcium entry: roles for Trp proteins. Proc. Natl. Acad. Sci. USA 93: 15195–15202, 1996.[Abstract/Free Full Text]
2. Boulay, G., X. Zhu, M. Peyton, M. Jiang, R. Hurst, E. Stefani, and L. Birnbaumer. Cloning and expression of a novel mammalian homolog of Drosophila transient receptor potential (Trp) involved in calcium entry secondary to activation of receptors coupled by the Gq class of G protein. J. Biol. Chem. 272: 29672–29680, 1997.[Abstract/Free Full Text]
3. Chevesich, J., A. J. Kreuz, and C. Montell. Requirement for the PDZ domain protein, INAD, for localization of the TRP store-operated channel to a signaling complex. Neuron 18: 95–105, 1997.[Medline]
4. Clapham, D. E. Calcium signaling. Cell 80: 259–268, 1997.
5. Gillo, B., I. Chorna, H. Cohen, B. Cook, I. Manistersky, M. Chorev, A. Arnon, J. A. Pollock, Z. Selinger, and B. Minke. Coexpression of Drosophila TRP and TRP-like proteins in Xenopus oocytes reconstitutes capacitative Ca²⁺ entry. Proc. Natl. Acad. Sci. USA 93: 14146–14151, 1996.[Abstract/Free Full Text]
6. Hardie, R. C., and B. Minke. The trp gene is essential for a light-activated Ca²⁺ channel in Drosophila photoreceptors. Neuron 8: 643–651, 1992.[Medline]
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8. Philipp, S., and V. Flockerzi. Molecular characterization of a novel human PDZ domain protein with homology to INAD from Drosophila melanogaster. FEBS Lett. 413: 243–248, 1997.[Medline]
9. Putney, J. W., Jr., and G. S. Bird. The inositol phosphate-calcium signaling system in nonexcitable cells. Endocr. Rev. 14: 610–631, 1993.[Abstract/Free Full Text]
10. Vaca, L., W. G. Sinkins, Y. Hu, D. L. Kunze, and W. P. Schilling. Activation of recombinant trp by thapsigargin in Sf9 insect cells. Am. J. Physiol. 267 (Cell Physiol. 36): C1501–C1505, 1994.
11. Xu, X.-Z. S., H.-S. Li, W. B. Guggino, and C. Montell. Coassembly of TRP and TRPL produces a distinct store-operated conductance. Cell 89: 1155–1164, 1997.[Medline]
12. Zhu, X., M. Jiang, and L. Birnbaumer. Receptor-activated Ca2+ influx via human trp3 stably expressed in human embryonic kidney (HEK) 293 cells. Evidence for a noncapacitative Ca²⁺ entry. J. Biol. Chem. 273: 133–142, 1998.[Abstract/Free Full Text]
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