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Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press; 2007.

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TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades.

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Chapter 2Multiple Mechanisms of TRPC Activation

National Institute of Environmental Health Sciences

Abstract

TRPC (canonical transient receptor potential) channels are vertebrate homologues of the Drosophila photoreceptor channel (TRP). Considerable research has been brought to bear on the seven members of this family, especially with regard to their possible roles in calcium entry. Unfortunately, the current literature presents a confusing picture, with different laboratories describing widely differing results and interpretations. It appears that ectopically expressed TRPC channels can be activated as a consequence of phospholipase C activation (by increases in diacylglycerols or by loss of phosphatidylinositol 4,5-bisphosphate), by stimulation of trafficking to the plasma membrane, or by depletion of intracellular Ca2+ stores. These diverse experimental findings arise because TRPC channels can, under both experimental as well as physiological conditions, be activated in three distinct ways, possibly depending on their subunit composition or signaling complex environment. The TRPCs may be unique among ion channel subunit families in having the ability to participate in the assembly and function of multiple types of physiologically important ion channels.

INTRODUCTION

The mammalian TRPC genes were identified from searches for homologues of the Drosophila trp gene [1–10]. The proteins encoded by the TRPC genes, like the parental Drosophila TRP protein, span the membrane six times [11] and contain a short hydrophobic sequence believed to be involved in forming the pore of the channel [12]. By analogy with other similar channels, it is believed that a functional TRPC channel will be formed by the four TRPC proteins coming together [12]; thus channels could be formed as homotetramers, if all four TRPCs are the same, or heterotetramers, if more than one kind of TRPC is involved. There appear to be restrictions as to which TRPCs can come together to form channels, although there is not complete agreement on what these restrictions are [12,13]. Hofmann et al. [12] found that when TRPC channels were exogenously expressed in HEK293 cells, the only permitted combinations were TRPC3, 6, and 7, or TRPC1, 4, and 5. However, a number of reports have found that TRPC1 and 3 can associate, with both exogenous and endogenous expressions [13–15]. Unlike previous studies of ion channel function, investigators attempted to understand the function of mammalian TRPC channels beginning only with knowledge of their coding sequence. There was considerable interest in this group because of the suspicion that they might be the long-sought store-operated or capacitative calcium entry channels [16]. In addition to TRPCs, the TRP superfamily includes two other major families: TRPMs (melastatin-related transient receptor potential channels), related structurally to melastatin, and TRPVs (vanilloid receptor-related transient potential channels), related to the vanilloid receptor, as well as more distantly related genes identified in genetic screens for specific diseases and whose physiological functions are less certain. Considerable progress has been made in our understanding of a number of TRP channels, especially those in the TRPV and TRPM families [17,18], and much of this information is reviewed in other chapters in this book. However, the function and regulation of TRPC channels have been more problematic, plagued with conflicting findings and interpretations. In this review I attempt to organize and rationalize some of these problems. I propose a paradigm that can help to explain the somewhat poorly predictable behavior of these widely expressed cation channels. In addition, I suggest that the apparently poorly predictable behavior of these channels in laboratory experiments might reflect expression of at least three distinct modes of regulation in their native physiological environments. A number of other aspects of TRPC channel regulation and activation mechanisms are reviewed in chapters by Birnbaumer, Gudermann, and Groschner.

TRPCS: MECHANISMS OF REGULATION IN TRANSFECTO

Based on sequence similarities, the seven TRPCs can be conveniently divided into four subgroups: TRPC1, TRPC2, and two additional groups, TRPC3, 6, and 7, and TRPC4 and 5. TRPC1 is most closely related to TRPC4 and 5 and is sometimes considered to be in the same group. TRPC2 is a pseudogene in humans but not in other mammalian species; there is evidence that TRPC2 can function as a store-operated channel in sperm [8,19], and is likely involved in vomeronasal function [20,21]. The body of literature on this channel is small by comparison to other TRPCs, however, and I will not discuss it further here. This topic is covered in the chapter by Dulac and Liman. The majority of research dealing with TRPCs has focused on the TRPC1/4/5 or TRPC3/6/7 groups. To date there is no clear evidence that TRPC5 behaves in a fundamentally different manner from TRPC4, and these two channels appear capable of association with TRPC1. Likewise, when compared side by side, TRPC3, 6, and 7 seem to behave similarly. There are important exceptions to these generalities, however, as noted below.

The TRPCs are so named [22] because this family is most closely related to the original Drosophila channel TRP (i.e., they are the “canonical” TRPs). Because Drosophila TRP was clearly activated downstream of phospholipase C and inositol 1,4,5-trisphosphate (IP3) generation in photoreceptor cells, Hardie and Minke [23] suggested that TRP might be the long-sought store-operated Ca2+ channel. The store-operated or capacitative calcium entry channels are activated by a process triggered by the depletion of intracellular endoplasmic reticulum Ca2+ stores [16,24]. Recent findings indicate that the sensor of intracellular Ca2+ store depletion may be the Ca2+-binding membrane protein, STIM1 [25,26]. Ironically, it is now very clear that store depletion is not the mechanism by which Drosophila TRP is activated in its native environment in photoreceptor cells [27]. The significance of this basic finding to the larger body of work on mammalian TRPCs perhaps should not be overlooked. Yet it is clear from phospholipase C (PLC)-deficient mutants that Drosophila TRP is activated in some manner downstream of PLC. It is most likely, although not proven, that a lipid mediator derived from PLC products activates TRP, perhaps the immediate breakdown product diacylglycerol (DAG), and it is also regulated in complex ways by the substrate of PLC, phosphatidylinositol 4,5-bisphosphate (PIP2) [27].

For the seven mammalian TRPCs, there is evidence that these channels are also activated in some manner downstream of PLC. Although initial studies suggested that TRPC1 and 3 were activated by store depletion [3], it was subsequently shown that activation resulted from the constitutive activity of the channels [28] (however, see reference [29]). One report suggested that IP3 and the IP3 receptor were involved in activating TRPC3 [30], but other laboratories failed to reproduce these results [7,31]. Likewise, the original studies on TRPC4 and TRPC5 presented evidence for activation by store depletion [5,6], but other researchers failed to reproduce these findings [32,33] (but see reference [34]). For the TRPC3/6/7 subfamily, the vast majority of published results suggests that DAG, produced upon phospholipase C activation, is the signal activating these channels [7,9,15,31,35–38]. For TRPC4 and 5, the case is not so clear. TRPC4 and 5 are highly sensitive to inhibition by protein kinase C, making it difficult to obtain evidence that DAG can activate. Indeed, while TRPC3/6/7 channels can be activated by exogenous DAG (usually oleyl acetyl glycerol, or OAG), OAG inhibits the activation of TRPC4 or 5, and this inhibition is blocked by inhibitors of protein kinase C [36]. Thus, if DAG is involved in the activation of TRPC4 or 5, there must be considerable compartmentalization of the signaling pathway to prevent concomitant inhibition by protein kinase C. An interesting possibility is that TRPC4 and 5 may be tonically inhibited by PIP2, such that PLC-mediated degradation of PIP2 relieves this inhibition, resulting in channel activation. Normally, PIP2 is thought to provide a positive regulation of TRPs [39–41]; however, for TRPV1, PIP2 appears to regulate negatively, although this is not thought to constitute a primary mechanism for channel activation [42].

As mentioned above, TRPC1 is often considered with TRPC4 and 5, as it is somewhat similar in sequence and is known to associate with TRPC4 and 5 to form heteromultimeric channels [12,13]. The actions of TRPC1 when expressed on its own are controversial; some researchers demonstrate activated ion channel behavior following expression of TRPC1 [3,4,43–45], while others find that the channel does not traffic to the plasma membrane correctly unless coexpressed with TRPC4 or 5 [12]. Interestingly, and important for arguments to be advanced below, Strübing et al. [46] found that heteromultimers of TRPC1 and TRPC5 had different electrophysiological properties from homotetramers of TRPC5.

A second mechanism that is important for activating TRPC channels involves regulation of their trafficking to the plasma membrane [47–49]. The published reports on this topic are not consistent with one another. However, it is clear from the study of Bezzerides et al. [49] that growth factors (EGF) activate the insertion of TRPC5 channels into the plasma membrane. Once the channels reach the membrane, subsequent maneuvers that activate the channels result in larger currents. Reports from other laboratories indicate that for other TRPCs, the translocation event per se leads to increased currents [47,48]. In either case, either constitutive or stimulated currents would be increased simply by increasing the number of channels and would not necessarily involve any further increase in open probability. The mechanism by which TRPC5 secretion is signaled does not seem to involve activation of PLC; instead it involves a pathway requiring phosphoinositide 3-kinase, Rac1, and phosphatidylinositol 4-kinase [49]. Finally, it is significant that only TRPC5 homotetrameric channels were activated in this manner. Heterotetramers containing TRPC5 and 1 did not translocate to the plasma membrane in response to EGF. This mechanism of regulation may apply to members of the broader TRP superfamily; there is at least one example of a TRPV channel that appears to be regulated in this way [50].

The third major mechanism that has been described for TRPC channel activation is the store-depletion or capacitative calcium entry mechanism. A number of studies have reported activation of TRPC channels by store depletion [3–6,30,38,51–61], and knockout or knock-down of TRPCs often reduces store-operated calcium entry [44,61–69]. Yet in many instances these channels clearly are not store operated [7,9,31,32,35,37,60,70,71]. It is becoming increasingly clear that the basis for the different behaviors is expression conditions. In DT40 B-lymphocytes, TRPC3 formed a store-operated channel at low levels of expression and formed a DAG-activated channel at higher levels of expression [60]. The loss of store-operated behavior at higher expression levels may result from inappropriate stoichiometry among members of a signaling complex [10], as has been argued previously for scaffolding proteins [72,73]. Significantly, the pharmacology of the channels differed in these two modes; the store-operated TRPC3 channels were much more sensitive to block by Gd3+ than the nonstore-operated channels [59]. Both TRPC7 [38] and TRPC5 [34] are store operated when stably expressed in HEK293 cells; in this case, the store-operated channels are either capable of activation by alternative, nonstore-operated mechanisms, or they coexist with channels that are activated by the nonstore-operated mechanisms. For TRPC7, it was demonstrated that this store-operated behavior is only seen with stable transfection. Transient transfection of HEK293 cells with TRPC7 results in channels that can only be activated by receptor activation or OAG, not by store depletion [38].

Thus, the available data demonstrate that, when ectopically expressed, TRPCs can be activated by one of three mechanisms: store depletion, phospholipase C (or its products), or channel translocation to the plasma membrane. The mode of activation seems to depend on the environment in which the subunit finds itself, including perhaps the nature of other subunits that compose the channel pore. This principle is most clearly illustrated by the case of translocation of TRPC5, which only occurs with TRPC5 homotetramers, not with TRPC5/1 heterotetramers [49]. It is also a logical interpretation of the observed difference in Gd3+ sensitivity of TRPC3 channels in store-operated as compared to phospholipase C-activated mode [59]. The question then arises: do these different modes of regulation occur with TRPC subunits when expressed in their native environments in untransfected cells?

MECHANISMS OF TRPC ACTIVATION IN SITU

The answer to that question seems to be, yes. There is now evidence that each of these modes of TRPC function in native, untransfected cells. In the case of store-operated channels, I have already mentioned the considerable number of examples of disrupted behavior of native store-operated channels by knock-down of TRPCs. However, a sticking point has been the failure of ectopically expressed TRPCs (or as yet any expressed ion channel) to faithfully reproduce the electrophysiological characteristics of Icrac (first described in detail in references [74] and [75]; for an example, see also reference [76]). However, it is clear that there are a variety of different kinds of store-operated channels [77–84], some of which have properties reminiscent of TRPCs. It is realistic to expect that TRPCs may contribute to the composition of store-operated channels in such instances. It is not out of the question to consider that TRPCs might play a role in Icrac channels, given the possibility of heteromultimers with drastically altered electrophysiological properties. Two reports have provided evidence for a role for TRPC1 [68] and TRPC3 [85] in Icrac.

There are examples of native channels that appear to be activated by diacylglycerols under physiological conditions [70,71,86–90]. In a particularly thorough study, Inoue et al. [87] investigated the role of TRPC6 in α-adrenergic-activated cation channels. These authors examined the electrophysiological and pharmacological characteristics of the endogenous cation entry controlled by α1-adrenoceptors in rabbit portal vein smooth muscle cells and found this cation entry to be reminiscent of that of the TRPC6 current when transiently expressed in HEK293 cells. Both the endogenous current and the current due to expressed TRPC6 could be activated by OAG in a PKC-independent fashion. Furthermore, TRPC6 mRNA and protein expression in the smooth muscle cells and knock-down of TRPC6 with antisense RNA in smooth muscle cells resulted in almost complete abrogation of the α1-adrenergic response. Similarly, Jung et al. [71] showed that vasopressin activates a non-CCE, nonselective cation current in the smooth muscle cell line, A7r5, resembling that seen with expression of TRPC6 in HEK293 cells. The DAG analog, OAG, activated the endogenous, agonist-sensitive current in A7r5 cells, and those cells were shown to express mRNA for TRPC1 and TRPC6 but not for other TRPC proteins. The authors then concluded that TRPC6 is likely a component of the endogenous agonist-activated channel in the A7r5 cell line.

There are far fewer examples of stimulated translocation of native TRPC channels, likely due to the rather recent discovery of this mode of activation. However, Bezzerides et al. [49] reported that native TRPC5 channels were localized to active growth cones in cultured hippocampal neurons (see also reference [91]). Surface expression of TRPC5 was increased by several different growth factors. TRPC1 was expressed in the cell soma and processes, and not in growth cones, consistent with the observation that only TRPC5 homotetramers undergo regulation through translocation.

SUMMARY

I previously suggested that TRPCs could form distinct types of channels, being regulated by either phospholipase C-dependent or store-depletion mechanisms [10]. Now the number of possible modes of regulation has expanded to three [92] (see Figure 2.1), and we cannot know that others will not be discovered. It is also becoming increasingly clear that this multiplicity of regulatory mechanisms does not simply reflect (at least in all cases) aberrant behavior due to overexpression but rather is indicative of true diversity of channel function in vivo. At least one of the factors that determines the function and regulation of TRPC channels appears to be the subunit composition of the assembled tetrameric channel. Additional factors may include partners in a signaling complex, such as regulatory subunits or scaffolding structures. The propensity of TRPC channels to intereact with the Ca2+ sensor, STIM1 [25,26], may be important for their regulation by Ca2+ store depletion. As argued previously [10], the ability of cells to utilize TRPCs in diverse ways may have significance beyond the ion channel field; such a multiplicity offers a means by which the complex mammalian organism can be assembled from what has turned out to be a surprisingly limited genome.

FIGURE 2.1. Activation mechanisms for calcium-permeable TRPC cation channels.

FIGURE 2.1

Activation mechanisms for calcium-permeable TRPC cation channels. TRPC channels can be activated in any of three distinct ways. (From left) Channels sequestered in a vesicular compartment can be translocated to the plasma membrane in response to growth (more...)

ACKNOWLEDGMENTS

The author gratefully acknowledges ideas and criticisms from Mohamed Trebak, Christian Erxleben, and Steve Shears.

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