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The Vanilloid Receptor Family of Calcium-Permeable Channels: Molecular Integrators of Microenvironmental Stimuli

Roger G. O’Neil and Rachel C. Brown

Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas 77030

	Abstract

 
The TRPV subfamily of calcium-permeable channels is widely distributed in sensory and nonsensory cells from nematodes to mammals. These channels can be variably activated by a diverse range of stimuli (osmotic/mechanical stress, noxious chemicals and heat, endogenous mediators) that often converge on the same channel. Evidence is presented that TRPV channels function as novel "molecular integrators" of diverse microenvironmental stimuli.

	Introduction

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

 
The regulation of intracellular calcium levels plays a critical role in controlling numerous calcium-dependent cellular processes such as gene expression, cell proliferation, muscle contraction, secretion, and cell shape/volume, to name a few (2, 9). Regulating intracellular calcium levels is complex, with multiple pathways for both influx and efflux from the cytoplasm. In general, calcium influx into the cytoplasm arises either from release of calcium from internal storage sites [primarily the sarcoplasmic/endoplasmic reticulum (SER)] via SER calcium-release channels (inositol trisphosphate receptors or ryanodine receptors) or from influx of calcium across the plasma membrane through calcium-permeable channels. Calcium efflux from the cytoplasm is effected by uptake of calcium into the SER by calcium pumps (the SER Ca²⁺-ATPase and other Ca²⁺-ATPases) and other storage sites or by extrusion across the plasma membrane by calcium pumps (plasma membrane Ca²⁺-ATPases) or sodium/calcium exchange mechanisms. The generation of calcium signals is complex, by nature, due to a myriad of calcium transport processes regulating calcium fluxes. Typically, intracellular calcium signals are generated by activation of plasma membrane calcium-permeable channels and/or activation of SER calcium-release channels.

Our understanding of the molecular basis of calcium signaling components has been markedly advanced with the discovery of calcium-release channels, the inositol trisphosphate receptors, and ryanodine receptors. However, progress into the identification and function of plasma membrane calcium-permeable channels has been comparatively slow, due in part to the apparent broad diversity of signaling mechanisms and plasma membrane calcium-permeable channels that appear to control calcium influx. The identity and role of some calcium influx channels, such as the voltage-activated calcium channels and the cyclic nucleotide-gated channels, has been well documented. However, numerous other pathways for calcium entry are apparent, particularly in nonexcitable cells. These pathways often lack molecular identification and elucidation of the underlying signaling mechanisms regulating the channel activity (2, 12).

The recent discovery of a new class of calcium-permeable cationic channels, the transient receptor potential (TRP) channel superfamily, has brought about major insights into the molecular entities and signaling mechanism controlling calcium influx in a broad range of cells (5, 8, 9, 12, 17). TRP channels are widely expressed in excitable and nonexcitable cells in both vertebrates and invertebrates and appear to represent primary pathways for regulated calcium entry. Whereas the first TRP channel was initially identified as a central component of the photoreceptor transduction complex in Drosophila, the subsequent discovery of homologs in mammals and C. elegans has led to an explosion in the identification of new TRP family channels, with more than 25 members now identified. The TRP superfamily has recently been classified into three main groups with a proposed fourth group being considered. The subfamilies are: TRPC, the classical or canonical-like TRP channels; TRPV, the vanilloid receptor-like channels; TRPM, the melastatin-like channels; and TRPP, the polycystic kidney disease 2 protein-like channels implicated in polycystic kidney disease. The functions of the TRP channels from the various subfamilies are only partially known but appear to underlie a broad range of functions, from sensory transduction, to secretion, to cell proliferation.

In the past few years, the TRPV subfamily has received increasing attention because of the expanding role that some members of this group appear to play in both sensory and nonsensory transduction functions. Various channels in this group have been shown to be uniquely sensitive to a broad range of noxious and nonnoxious environmental stimuli, including heat, "hot" peppers, and osmosensory and mechanosensory stimuli. Interestingly, the channels appear to be points of convergence of multiple stimuli and, as such, may function as "molecular integrators" (3, 8), a rather novel property for a single macromolecular entity in biological systems. The basic properties and function of the TRPV channels and the emerging evidence pointing to some members of this subfamily as integrators of microenvironmental stimuli are discussed below.

	Properties of the TRPV channel subfamily

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

 
The structure of the TRPV channels is depicted in Fig. 1. Like other TRP members, the channels are characterized by six transmembrane-spanning domains with relatively long NH₂ terminals and COOH terminals (5, 8, 17). A short hydrophobic segment between transmembrane spans 5 and 6 is thought to give rise to a "pore loop" forming part of the channel pore. The NH₂ terminals contain 2–5 ankyrin repeat domains (ARD), as potential sites of protein interactions, and several potential protein kinase C (PKC)/protein kinase A (PKA) phosphorylation sites. Some regions of the NH₂ terminals (ARDs) and transmembrane segments are relatively conserved, whereas the COOH-terminal tail is unconserved. By analogy to potassium channels, the functional TRPV channels are likely to be made up of tetramers of TRPV subunits, possibly heterotetramers. The TRPV channels function largely as calcium-permeable cation channels with varying calcium selectivity. Although most members of the family are characterized as having only a modest calcium selectivity over monovalent cations, TRPV5 and TRPV6 are characterized by a highly calcium-selective pore. The tissue distribution and known functions of the channel members are, in general, quite variable, although overlapping functions continue to be discovered.

View larger version (30K): [in this window] [in a new window]   FIGURE 1. Topological model of vanilloid receptor-like transient receptor potential (TRPV) channel structure. The channel is proposed to have 6 transmembrane domains (TM1–TM6), a pore loop (PL), and a long NH2 terminal and COOH terminal, both cytoplasmic. The NH2 terminal has 2–5 ankyrin repeat domains (ARD), with 3 ARDs being typical.

	The mammalian TRPV channels: sensory and nonsensory functions

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

A particularly intriguing aspect of the emerging nature of TRPV1 regulation is the apparent sensitization of TRPV1 to two or more stimuli and to endogenous modulators. Exposure of TRPV1-expressing cells to acidic conditions sensitizes the channel to activation by heat, reducing the threshold of activation to the normal physiological range (see Refs. 1 and 3). Likewise, acidic conditions sensitize the channel to activation by capsaicin. Alternatively, exposure of cells to capsaicin can sensitize the channel to activation by acidic conditions (15). Furthermore, addition of low levels of the phorbol ester phorbol 12-myristate 13-acetate (PMA) or exposure to bradykinin to activate phospholipase Cß and the subsequent production of diacylglycerol (DAG) can lead to sensitization of the channel by a PKC-dependent process. This potentiation or cross-sensitization indicates a more complex level of integration, where endogenous modulators and/or exogenous stimuli may be regulating the process of convergence of exogenous signals. Indeed, it has been suggested that the apparent sensitization of the channel could lead to the phenomenon of hyperalgesia associated with inflammation, in which the release of bradykinin and protons from inflamed tissue would lead to sensitized activation of TRPV1 and the generation of hypersensitivity to heat (1, 3).

Three other mammalian TRPV channels, TRPV2, TRPV3, and TRPV4, have also recently been shown to be activated by heat, but with a broad range of thresholds: >53°C for TRPV2, >31–39°C for TRPV3, and >25–33°C for TRPV4 (see Refs. 1 and 17). This broad range of thermal sensitivities among the TRPV1–TRPV4 channel group may underlie the wide range of thermal sensations known in mammals. Since TRPV1, TRPV2, and TRPV3 are widely expressed in the thermal-sensitive dorsal root ganglia and trigeminal ganglia, whereas TRPV3 and TRPV4 are also expressed in another thermal-sensitive tissue, skin keratinocytes (4, 14), the concept of these four channels playing a integrated role in thermal sensation seems highly likely. However, it remains for future studies to determine the specific roles each of these channels may actually play in thermal sensation and how these channels may participate in altered states of thermal sensation, such as hyperalgesia, during periods of inflammation or local cell injury. Nonetheless, it is apparent that this grouping of TRPV channels may represent another important layer of integration, the integration among channels to provide thermal sensation over a broad range of thermal stimuli.

"...TRPV2, TRPV3, and TRPV4 may have a much broader range of functions in addition to thermal sensation..."

TRPV2, TRPV3, and TRPV4 may have a much broader range of functions in addition to thermal sensation. Whereas evidence of such behavior has not been documented for TRPV2 and TRPV3, TRPV4 is sensitive to a broad range of stimuli. TRPV4 is widely expressed in both excitable and nonexcitable cells. It is highly expressed in kidney and tracheal epithelial cells and more moderately expressed in osmosensory cells of the circumventricular organs in the hypothalamus, mechanosensory cochlear hair cells and vibrissal Merkel cells, heart and vascular endothelial cells, dorsal root and trigeminal ganglia, and skin epidermal keratinocytes, to name a few (see Refs. 1, 13, 17). It also has a broad distribution in other tissues, including liver, lung, spleen, sweat glands, and fat tissue. This wide distribution in tissues and cells may indicate that the channel may have multiple modes of regulation. Indeed, TRPV4 was originally thought to be involved in osmosensation since the channel was initially shown to be activated by modest hypotonic swelling. Others soon demonstrated, however, that the channel could also be activated by warm temperatures (7, 19) and by the non-PKC-activating phorbol ester, 4-phorbol 12,13-didecanoate (4-PDD) (18). The actions of 4-PDD appear to be selective for TRPV4 and may involve direct binding to the channel, although the mechanism of activation has not been fully defined. Most recently, it was demonstrated that temperature may sensitize the channel to other stimuli (6). At physiological temperatures (37°C), as opposed to room temperature, the channel not only displays a robust response to activation by hypotonic stress and 4-PDD but can also be strongly activated by mechanical stress (shear stress) and PMA, responses absent or weakly apparent at room temperature. The effect of shear stress clearly points to a role of this channel in mechanosensory phenomena. Furthermore, the actions of PMA were dependent on PKC, as anticipated, but the actions of hypotonic swelling and shear stress were not, demonstrating the presence of both PKC-dependent and non-PKC-dependent signaling pathways. Although the mechanism of activation by hypotonic swelling and mechanical stress is not known, the mechanism appears to differ fundamentally from that observed for a hypotonic swelling/stretch-activated calcium channel in renal proximal tubule cells, which was regulated by PKC-dependent processes (11, 20). The demonstration of a PKC-dependent signaling pathway regulating TRPV4 raises the likelihood that ligand receptors that are coupled to phospholipase Cß and the generation of DAG, leading to activation of PKC, may also regulate TRPV4 activation. Hence, like TRPV1, multiple stimuli again appear to converge on this single channel, demonstrating that it too functions as a molecular integrator of multiple chemical and physical stimuli.

The last two members of the mammalian TRPV channels, TRPV5 (ECaC1) and TRPV6 (ECaC2), are more distant members of the TRPV channels (Fig. 2) and appear to display somewhat different functional properties (5, 17). The channels are highly calcium selective, as opposed to the other TRPV channels, and hence appear to display unique pore properties. The channels are widely expressed in epithelial cells, including in the gastrointestinal tract, kidney, pancreas, prostate gland, mammary gland, and sweat gland, and may represent the apical membrane calcium channel in calcium-reabsorbing epithelial cells (5). The channels are constitutively active, appearing to give rise to ongoing calcium reabsorption, and are inactivated by increased intracellular calcium levels, supposedly through a calmodulin-dependent process. On the basis of analogy to native tissues expressing these channels, it is speculated that certain peptide hormones may be exerting regulatory control of these channels, although this remains to be demonstrated. On a long-term basis, the expression of both channels appears to be under the control of calciotropic hormones (vitamin D, estrogen) and dietary calcium. Whether other undefined stimuli regulate the channels over the short term remains to be determined.

View larger version (16K): [in this window] [in a new window]   FIGURE 2. Dendrogram of TRPV channels showing phylogenetic similarities. Protein sequences were pulled from the NCBI database and compared by using the ClustalW multi-sequence alignment utility. Species (h, human; ce, Caenorhabditis elegans; dm, Drosophila melanogaster), channel name, protein size [in amino acids (aa)], and accession numbers are as follows: hTPRV1 (838 aa, NM_080704), hTRPV2 (764 aa, NM_016113), hTRPV3 (790 aa, NM_145068), hTRPV4 (871 aa, NM_021625), hTRPV5 (729 aa, NM_019841), hTRPV6 (557 aa, NM_014274), ceOSM-9 (937 aa, AF031408), ceOCR-1 (790 aa, NM_073347), ceOCR-2 (900 aa, NM_068979), ceOCR-3 (789 aa, NM_078119), ceOCR-4 (769 aa, NM_068771), dmNan (833 aa, AY262004), and dmCG4536 (1123 aa, NM_132125). The dendrogram from the ClustalW analysis indicates that the human TRPV channels split into 2 major groups, 1 containing TRPV1–TRPV4 (42–50% identity), the other containing TRPV5 and TRPV6 (76% identity). C. elegans and D. melanogaster sequences fall into three major groups, the first containing ceOSM-9 and dmCG4536 (41% identity), the second containing ceOCR-1, -2, and -3 (43–52% identity), and the third containing OCR-4 and dmNan (36% identity).

	The nematode OSM-9 channel and related subunits: diverse sensory functions

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

In C. elegans, the combined expression of OSM-9 with OCR-2 in defined neurons is necessary for numerous sensory functions (16). For example, in the C. elegans’ amphid sensory neurons, AWA and ASH, it was clearly demonstrated that the combined expression of OSM-9 and OCR-2 leads to key sensory functions, including olfaction (noxious odors) in AWA and ASH and mechanosensation (nose touch) and osmosensation (high osmolarity) in ASH. Other heterologous expression patterns may define other functions, although these have not been clearly defined. Regardless, it is apparent that, as observed for mammalian TRPV channels, TRPV channel homologs in C. elegans respond to a diverse range of sensory stimuli that converge on the same channel or combination of channel subunits. Hence, the function of the TRPV channels at the invertebrate level also displays properties of unique molecular integrators of diverse stimuli.

	The Drosophila Nan channel: mechanosensory transduction

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

 
The chordotonal organ of many insect ears is the sensory organ in which sound-induced antennal/tympanal vibrations are transmitted to ciliated sensory neurons that, in turn, transduce the signal into receptor potentials. The Drosophila no mechanoreceptor potential C channel, a distant TRP channel family member, is expressed in the chordotonal organ and appears to play a role in tactile bristle responses but not in the sound-evoked antennal response. Recently, homology searches with the Drosophila genome identified two additional genes that fall within the TRPV channel family: Drosophila CG4536 and CG5842 (16). The cDNA from CG5842, which encodes the Nanchung protein (Nan), has been expressed in heterologous expression systems and displays typical calcium-permeable cationic properties of TRPV channels (10). Nan has the characteristic TRPV structure, including five ARDs in the NH₂ terminus. The channel protein is most similar to the C. elegans OCR-4 (37% identity), with decreasing similarity to the other OCR proteins, CG4536 and OSM-9, and the mammalian TRPV channels (Fig. 2).

Drosophila Nan has been shown to be expressed exclusively in the mechanosensory ciliary segments of the chordotonal organ (10). Nan mutants completely lack antennal sound-evoked potentials, demonstrating that Nan is an essential component for mechanotransduction in the chordotonal organ. When Nan is expressed in heterologous expression systems, the channel can be activated by hypotonic stress but not by capsaicin or heat. Hence, the Nan channel appears to display both osmosensory and mechanosensory functions similar to that observed for the Drosophila OSM-9 and mammalian TRPV4 and may be the channel underlying sound transduction in Drosophila. The recent demonstration that the mammalian TRPV4 is sensitive to activation by mechanical stress (shear stress) in a heterologous expression system (6) provides strong evidence that TRPV4 channels, and perhaps TRPV4-related proteins such as OSM-9 and Nan, are transducers of mechanical stimuli. This view is further supported by the evidence that, like Nan, the mammalian TRPV4 channel is also expressed in many mechanosensory cells, including cochlear hair cells, vibrissal Merkel cells, some mechanosensory ganglia (see Ref. 13), and vascular endothelial and kidney epithelial cells that are sensitive to shear stress (see Ref. 6). The Nan channel would, therefore, appear to be sensitive to several forms of mechanical and osmotic stress that may be part of the same signal transduction pathway. These initial studies indicate that Nan, like OSM-9, may represent an early evolutionary step in functional integration of diverse signals.

	TRPV channels as molecular integrators

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

 
It is apparent from the available evidence, as heretofore discussed, that many TRPV channels appear to function as molecular integrators of diverse chemical and physical stimuli leading to a common transduction process, i.e., activation of the channel. This integration is a strongly conserved evolutionary feature for this channel subfamily, because it is already highly developed at the level of the nematode, where diverse sensory modalities converge on the same signal-transducing channels in sensory neurons. This feature is not only conserved in mammals but appears to have evolved into a more complex process in higher organisms, because the TRPV channels are now expressed in both sensory and "nonsensory" cells and are activated by a broader range of stimuli, including multiple chemical and physical components and endogenous signaling modulators. A cellular model demonstrating the diverse range of stimuli and integration of converging signaling pathways regulating the mammalian TRPV4 channel is given in Fig. 3.

View larger version (25K): [in this window] [in a new window]   FIGURE 3. Molecular model showing potential converging pathways regulating TRPV4 channels as a representative example of molecular integration of microenvironmental stimuli. TRPV4 channels are permeable to calcium and monovalent cations such as sodium. The channel appears to be regulated by at least two pathways, one protein kinase C (PKC)-dependent, the other PKCindependent, although other pathways are likely. The range of stimulants for the two pathways are indicated. R, hormone/ligand receptor; G, G protein; PLC, phospholipase Cß; DAG, diacylglycerol; IP3, inositol trisphosphate; P, potential phosphorylation site; ?, potential signaling pathways controlling activation of TRPV4.

Finally, it would be anticipated that the same global integrative properties of the TRPV channels may also give rise to a diversity of responses at a local level, depending on the particular microenvironmental conditions imposed on the local cell or tissue. Differences in microenvironmental conditions, such as in temperature, shear stress, and acidity, for example, may lead to a modulated response of some TRPV channels exposed to the altered microenvironmental conditions, compared with that of the same TRPV channels in cells not exposed to the modified conditions. Indeed, such a phenomenon may underlie the sensation of pain and hyperalgesia to heat in inflamed tissue (1). In this scenario, bradykinin is released in inflamed tissue that, in turn, will lead to the generation of DAG and activation of PKC. In sensory neurons expressing TRPV1, activation of PKC will likely lead to phosphorylation of the channel, resulting in sensitization of the channel and a lower threshold temperature. Consequently, modest nonnoxious heat can now lead to local activation of TRPV1 channels, giving rise to an enhanced sensation of pain, or hyperalgesia, at the local site. The response of many TRPV channels would, therefore, likely be altered by the particular microenvironmental setting surrounding the cell or tissue.

In summary, it is evident that many TRPV channels from nematodes to mammals function as molecular integrators of microenvironmental stimuli. This integration can occur at several hierarchical levels, from the integration of converging signals at the single-channel macromolecular level, to integration among channel subtypes within the same cell/tissue, to integration among different cells and tissues expressing the same or different channels. These apparent levels of integration may vary among the specific subtypes of TRPV channels, with some subtypes, such as TRPV5 and TRPV6, possibly showing little integration and other subtypes, such as TRPV1–TRPV4, OSM-9/OCR, and Nan, showing a broad range of integration of diverse stimuli.

	Acknowledgments

 
This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-40545) and the American Heart Association, Texas Affiliate (Grant-In-Aid 0150758Y) to R. G. O’Neil and by a National Institute of Neurological Disorders and Stroke National Research Service Award (F32-NS-43052) to R. C. Brown.

	References

Top Introduction Properties of the TRPV... The mammalian TRPV channels:... The nematode OSM-9 channel... The Drosophila Nan channel:... TRPV channels as molecular... References

 

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