View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 12 Juneprovided 2012 by Frontiers - Publisher Connector doi: 10.3389/fimmu.2012.00150 The role ofTRP proteins in mast cells

Marc Freichel*, Julia Almering and VolodymyrTsvilovskyy

Pharmakologisches Institut, Universität Heidelberg, Heidelberg, Germany

Edited by: Transient receptor potential (TRP) proteins form cation channels that are regulated through Ulrich Blank, Université Paris-Diderot strikingly diverse mechanisms including multiple cell surface receptors, changes in tem- Paris 7, France 2+ 2+ perature, in pH and osmolarity, in cytosolic free Ca concentration ([Ca ]i), and by Reviewed by: Marc Benhamou, Institut National de phosphoinositides which makes them polymodal sensors for fine tuning of many cellu- la Santé et de la Recherche Médicale, lar and systemic processes in the body. The 28 TRP proteins identified in mammals are France classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP.When acti- Pierre Launay, Institut National de la vated, they contribute to cell depolarization and Ca2+ entry. In mast cells, the increase of Santé et de la Recherche Médicale, 2+ 2+ France [Ca ]i is fundamental for their biological activity, and several entry pathways for Ca and 2+ 2+ *Correspondence: other cations were described including Ca release activated Ca (CRAC) channels. Like 2+ Marc Freichel, Pharmakologisches in other non-excitable cells, TRP channels could directly contribute to Ca influx via the Institut, Universität Heidelberg, Im plasma membrane as constituents of Ca2+ conducting channel complexes or indirectly by Neuenheimer Feld 366, 69120 shifting the membrane potential and regulation of the driving force for Ca2+ entry through Heidelberg, Germany. 2+ e-mail: [email protected] independent Ca entry channels. Here, we summarize the current knowledge about the heidelberg.de expression of individualTrp genes with the majority of the 28 members being yet identified in different mast cell models, and we highlight mechanisms how they can regulate mast cell functions. Since specific agonists or blockers are still lacking for most members of the TRP family, studies to unravel their function and activation mode still rely on experiments using genetic approaches and transgenic animals. RNAi approaches suggest a functional role for TRPC1, TRPC5, and TRPM7 in mast cell derived cell lines or primary mast cells, and studies using Trp gene knock-out mice reveal a critical role for TRPM4 in mast cell activation and for mast cell mediated cutaneous anaphylaxis, whereas a direct role of cold- and menthol-activated TRPM8 channels seems to be unlikely for the development of cold urticaria at least in mice.

Keywords:TRP proteins, cation channels, Ca2+ signaling, mast cell activation

CA2+ ENTRY PATHWAYS AND MAST CELL ACTIVATION antigen-mediated mast cells degranulation is dependent on Ca2+ In mast cells, the increase of free cytosolic Ca2+ regulates a vari- influx through Ca2+ channels that are permeable for Sr2+/Ba2+ ety of cellular processes including degranulation with release of (Ma and Beaven, 2009, 2011). Distinct temporal and spatial pat- preformed inflammatory mediators (Ozawa et al., 1993), pro- terns of the increase in intracellular Ca2+ concentration triggered duction of eicosanoids such as leukotrienes (Chang et al., 2006), by individual Ca2+ mobilizing mast cell activators may explain activation of transcription factors including the nuclear factor the specificity of mast cell responses. For example, differences in of activated T cells (NFAT; Kar et al., 2011), and synthesis of the amplitude and duration of Ca2+ signals in response to dif- cytokines (Plaut et al., 1989) as well as cytoskeletal rearrangements ferent stimulants differentially influence histamine secretion or required for migration of mast cells and chemotaxis (Hartmann production of eicosanoids (van Haaster et al., 1995). Also, it was et al., 1997). Mast cell derived mediators can evoke both patholog- shown that, under certain conditions, mast cells can be stimulated ical inflammatory responses in allergic or autoimmune diseases to undergo chemotaxis without degranulation (Taub et al., 1995). but they can also have protective functions, e.g., by induction of More recent work has revealed that a range of mast cell responses innate immune responses leading to clearance of pathogens or are activated by spatially restricted Ca2+ signals just below the by degrading endogenous and exogenous toxins (Marshall, 2004; plasma membrane (Di Capite and Parekh, 2009; Kar et al., 2011). Galli et al., 2005; Metz and Maurer, 2007). The importance of Although mast cells have numerous functions beyond the extracellular Ca2+ as a requirement for anaphylactic release of his- development of allergies, studies of mast cell signal transduction tamine from rat peritoneal mast cells was already shown in 1972 have mainly been driven by the central role of these cells in allergic (Foreman and Mongar, 1972), and it could be shown that Ca2+ inflammatory responses (Metcalfe et al.,1997). The manifestations could be replaced by Sr2+ or Ba2+ to achieve mast cell degranula- of mast cell-driven allergic reactions are considered to be mainly tion (Foreman et al., 1977). Later, it was shown that substantial a consequence of the release of pro-inflammatory mediators fol- amounts of Ca2+ in the external medium (i.e., >50 μM) was lowing antigen-induced aggregation of high-affinity receptors for absolutely required for degranulation in rat basophilic leukemia IgE (FcεRI), expressed at the mast cell surface. FcεRI cross-linking (RBL)-2H3 cells (Beaven et al., 1984) leading to the concept that activates a large number of signaling molecules (Blank and Rivera,

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2004; Gilfillan and Tkaczyk, 2006). A major downstream target cell activators has not been analysed so far. This suggests that other is phospholipase Cγ1 (PLCγ1), which catalyzes the hydrolysis of channel proteins – especially members of the TRP family such as 2+ phosphatidylinositol (4,5) bisphosphate (PIP2) to diacylglycerol TRPC5 (Ma et al., 2008) – might contribute to Ca entry either (DAG) and inositol (1,4,5) trisphosphate (IP3). DAG and IP3 pro- as part of an Orai/TRP channel complex (Liu et al., 2003, 2007; mote protein kinase C (PKC) activation and release of Ca2+ from Liao et al., 2007; Yuan et al., 2007) or independently. intracellular stores, respectively, followed by an influx of Ca2+ In addition to activation of FcεRI and depletion of intracel- from the extracellular space. Also in other non-excitable cells the lular Ca2+ stores there is increasing evidence that receptors for depletion of intracellular Ca2+ stores correlates with influx of other ligands such as adenosine, endothelin-1, stem cell factor Ca2+ from the extracellular space suggesting that the amount of (SCF), lysophosphatidylcholine (LPC), sphingosine-1 phosphate Ca2+ in the stores controls the extent of Ca2+ influx, a process (S1P), substance P, and others, which markedly influence mast that was called store-operated Ca2+ entry (SOCE) or capacitative cell activation in a physiological setting, do also induce elevations 2+ 2+ Ca entry (CCE; Putney, 1986; Parekh and Putney, 2005) and of [Ca ]i. These receptors can either potentiate FcεRI-mediated described later also in mast cells (Putney, 1986; Ali et al., 1994; mast cell activation or, by themselves, stimulate the release of mast 2+ 2+ Falcone and Fewtrell, 1995). Ionic currents mediating this Ca cell mediators. The pathways leading to elevation of [Ca ]i fol- influx were first characterized by Hoth and Penner (1992, 1993) in lowing stimulation of these receptors are still poorly characterized, RBL cells and rat peritoneal mast cells. The physiological hallmark and particularly it is not known whether or to which degree the of the underlying channel is a high selectivity for Ca2+ over other resultant receptor-activated Ca2+ entry is mediated by store deple- cations and its activation by depletion of intracellular Ca2+ stores, tion. Receptor stimulation using substance P or compound 48/80 2+ 2+ 2+ e.g., by IP3 and chelation of cytosolic Ca .TheCa selectivity leads to a Ca influx through non-selective cation channels in rat of Ca2+ release activated Ca2+ (CRAC) channels is similar to that peritoneal mast cells (Penner et al., 1988; Kuno and Kimura, 1992; of voltage-activated Ca2+ channels (VDCC) which were shown Fasolato et al., 1993). Recently, an additional mechanism for regu- to be expressed and to modulate mast cell activation (Yoshimaru lation of Ca2+ entry in mast cells has been discovered that does not et al., 2009), but the conductance of CRAC channels is much lower. rely on mast cell intrinsic mechanisms such as receptor stimulation Also, replacement of external Ca2+ with Sr2+ or Ba2+ resulted in by soluble mediators or regulation of the driving force for Ca2+ a decline in ICRAC activity (Zweifach and Lewis, 1996) indicating entry but on the interaction with another cell type: it could be that CRAC channels cannot represent the exclusive Ca2+ entry shown that binding of OX40 expressed on regulatory T cells to the channel mediating Ca2+ dependent mast cell degranulation. The mast cell based receptor OX40L inhibits Ca2+ entry by an increase desire to identify the molecular nature of SOCE was and still is the of intracellular cAMP levels in mast cells (Gri et al., 2008). The motivation for many workers to characterize mammalian transient molecular constituents of the Ca2+ conducting channels regulated receptor potential (TRP) channels. However, the pore properties by this new pathway are unknown like those channels activated of most TRP channels that have been studied in detail, including by the numerous Ca2+ mobilizing agonists described above, but TRPV6, which was identified in primary murine and human mast members of the TRP family are potential candidates also for these cells (Turner et al., 2007), and TRPV5, appeared not to match the Ca2+ entry pathways. pore properties of CRAC channels (see below and Owsianik et al., 2006b). Recently, Orai1 (also known as CRACM1) was identified TRP PROTEINS FORM CATION CHANNELS as the pore-forming CRAC channel subunit (Feske et al., 2006; Vig Transient receptor potential channels are a large and function- et al., 2006; Lewis, 2007) and another protein called stromal inter- ally heterogeneous family of cation-conducting channel proteins, action molecule 1 (Stim1) was shown to represent the Ca2+ sensor which are activated and regulated through strikingly diverse mech- coupling the process of depletion of intracellular Ca2+ stores with anisms. The first TRP channel gene was discovered in Drosophila Ca2+ influx across the plasma membrane through CRAC chan- melanogaster (Montell and Rubin, 1989) in the analysis of a fly nels (Lewis, 2007). Orai1 and its homologs Orai2 and Orai3 were mutant whose photoreceptors failed to retain a sustained response shown to be expressed in RBL-2H3 cells and bone marrow-derived to maintained light stimuli. In mammals, TRP proteins were iden- mast cells (BMMCs; Gross et al., 2007). SOCE is substantially tified in most cases by their sequence homology. Nevertheless, decreased in Orai1-deficient BMMCs (Gwack et al., 2008), and some TRPs were identified by expression cloning, e.g., TRPV1 the FcεRI-mediated Ca2+ entry is reduced by 70%, while the cells as the receptor for vanilloids such as capsaicin, or by positional completely lack detectable Ca2+ (CRAC) currents (Vig et al.,2008). cloning efforts to identify genes disrupted in human diseases, e.g., Interestingly, in this study it was concluded that Ca2+ release TRPML1 (also designated as mucolipin, MCOLN1, ML1) as a from intracellular stores is unchanged in Orai1-deficient BMMCs gene that is mutated in mucolipidosis type IV or TRPP2 (also (Vig et al., 2008) suggesting that ORAI1 proteins are non-critical designated as polycystin-2, PKD2, PC2) in autosomal polycystic components for the refilling of these Ca2+ stores. The relative con- kidney disease. tribution of Orai2 and Orai3 for Ca2+ entry in mast cells is still The mammalian 28 TRP proteins are classified according unclear. Although these results support the conclusion that ORAI1 to structural homology into six subfamilies: TRPC (canonical), (CRACM1)-proteins build the Ca2+-selective channels responsi- TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML ble for the majority of Ca2+ entry into mast cells, there is still some (mucolipin), and TRPP (polycystin; Montell et al., 2002; Clapham residual Ca2+ entry in Orai1-deficient BMMCs after stimulation et al., 2005; Wu et al., 2010). All TRP channels are assumed to have of the FcεRI or store depletion. Ca2+ entry in Orai1-deficient six-transmembrane (6TM) polypeptide subunits that assemble as mast cells following activation with other Ca2+ mobilizing mast tetramers to form cation-permeable pores (Owsianik et al.,2006a).

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Most TRP channels show little voltage dependence and are non- approaches as well as Western Blot analysis or immunocytochem- 2+ + selective with a permeability for Ca over Na (ratio PCa/PNa) istry for which commercial anti-TRP antibodies were used in most below 10. Therefore, TRP channels are not only important for cases. For the latter approach, it has to be mentioned that many Ca2+ entry via the plasma membrane but play also an important commercial suppliers pass the burden of antibody validation to the role in electrogenesis regulating the driving forces for Ca2+ entry end user and that the specificity of the antibodies used was rarely via other Ca2+-permeable channels. Table 1 (Venkatachalam and tested rigorously in preparations of cells/tissues that do not express Montell, 2007; Gees et al., 2010) gives an overview about the per- the target protein at all (Meissner et al., 2011). The functional meability of channels formed by individual TRP proteins, but it role of individual TRP proteins in mast cells was analysed using has to be emphasized that most of these information is based on TRP channel antagonists, RNAi approaches, and TRP deficient studies of heterologously expressed channel proteins and the char- mouse models. Regarding RNAi approaches it needs to be noted acteristics of those channels may differ significantly from native that – despite the merits of this technology – off-target effects are channel complexes existing in primary cells since the ectopically not unusual, and were also described in a study where transfec- expressed channel proteins do not necessarily act in accordance tion of a Trpm7 -specific siRNA achieved complete suppression of with the native cellular context as in primary cells. Trpm7 mRNA in other primary cells but also significantly reduced Transient receptor potentials are expressed in many (if not in TRPM2 expression levels (Aarts et al., 2003). Secondly, the control all) excitable and non-excitable cells and are involved in sensing of the effectiveness of RNAi approaches requires specific antibod- of a variety of environmental stimuli such as temperature, pH, ies against the target TRP protein to avoid the situation that at the osmolarity, pheromones, taste, and plant compounds. TRP chan- same time a poorly characterized RNAi experiment is controlled nels participate in numerous cellular processes to determine organ by non-validated antibodies and vice versa. Reports using mast and integrative body functions, and several mutations in Trp genes cells derived from mice with targeted deletion of Trp genes are appear to be causative factors in rare heritable channelopathies restricted until now to cells from mice with ubiquitous inactiva- (Freichel and Flockerzi, 2007; Nilius and Owsianik, 2010). tion of individual Trp genes, in which the observed phenotype may Although the search for natural ligands and chemical modulators be affected by compensatory mechanisms. of TRP channels as therapeutics has been intensified in the last years, specific agonists or blockers are still lacking for most mem- TRPC CHANNELS bers of the TRP family until now. Therefore, genetic approaches The mammalian members of the TRPC family can be are still required to advance a causal understanding of their physio- divided into three subfamilies on the basis of functional logical functions in primary cells, in organs, for systemic functions similarities and sequence homology: TRPC1/TRPC4/TRPC5, of organisms and for disease states. These approaches include TRPC3/TRPC6/TRPC7, and TRPC2. Physical interaction between over-expression of dominant-negative variants, antisense oligonu- the TRPC family members was studied by co-immunoprecipitation cleotides, and RNAi as well as targeted deletion of the gene of and FRET experiments with heterologously expressed proteins interest using homologous recombination (Freichel et al., 2011). and using immunoprecipitation from brain protein fraction using Another obstacle that hinders the analysis of endogenous TRP antibodies directed against peptides derived from TRPC proteins channels is that specific antibodies are rare for most TRP proteins and revealed that TRPC1, TRPC4, and TRPC5 may coassemble (Meissner et al., 2011) and, accordingly, this impedes investiga- as well as TRPC3, TRPC6, and TRPC7 (Lintschinger et al., 2000; tions of the assembly and localization of TRP channels, but also Strubing et al., 2001; Goel et al., 2002; Hofmann et al., 2002). In the control of the effectiveness of RNAi approaches. embryonic rat brain,it was found that TRPC1,TRPC4,and TRPC5 interact with TRPC3 and TRPC6 (Strubing et al., 2003). All TRPC EXPRESSION AND POSTULATED FUNCTIONS OF TRP proteins seem to be activated by stimulation of G-protein-coupled PROTEINS IN MAST CELLS receptors or receptor-tyrosine kinases. The activation of the PLC In the following we highlight key features regarding activation and pathway leads to the opening of TRPC channels but in paral- functions of individual members of the TRP subfamilies, concern- lel to stimulation of IP3 receptors and subsequent depletion of ing their expression in mast cell models and established or postu- intracellular Ca2+ stores and, hence, SOCE. This raised the issue lated mast cell functions. Table 1 systematically summarizes infor- whether TRPC proteins are constituents of cation channels medi- mation about the permeability,mode of activation,and the biolog- ating SOCE, and a contribution of TRPC proteins to SOCE has ical functions in native systems as revealed by mouse models for the been suggested very early after their first discovery (Hardie and individual mammalian TRP proteins. For more detailed informa- Minke, 1993). In principle, over-expressed mammalian TRPCs tion regarding structure, gating, special functional aspects of splice haveallbeenreportedtobeactivatedbystoredepletion(for variants, TRP channelopathies, and citations of the wealth of orig- review see, e.g., Venkatachalam et al., 2002). However, the depen- inal manuscripts about mammalian TRP proteins since their first dence of TRPCs on store depletion requires special conditions. description and functional characterization in 1995/1996 (Wes For instance, TRPC3 channels, which are activated directly by et al., 1995; Zhu et al., 1995; Philipp et al., 1996), we refer to PLC-derived DAG in many expression systems, were also reported various excellent recent review articles (Venkatachalam and Mon- to be activated by reduction of the filling state of intracellular tell, 2007; Gees et al., 2010; Nilius and Owsianik, 2010; Wu et al., Ca2+ stores (Kiselyov et al., 1998; Vazquez et al., 2003), but the 2010). The current knowledge about the expression of TRP pro- ability of TRPC3 to contribute to SOCE was only found when teins in different cell lines and primary mast cell models (Table 2) it was expressed at low densities (Vazquez et al., 2003; Yildirim is based on analysis using RT-PCR,gene arrays or quantitative PCR et al., 2005). The underlying cause for this phenomenon has not

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Table1|Properties of channels formed by mammalianTRP proteins.

Subtype Selectivity PCa2+/PNa+ Activation/modulation of activity Consequences ofTRP-deletion in mice

TRPC1 ∼1 PLC activation, store depletion, conforma- Elevated body weight, impaired salivary gland fluid secretion tional coupling, mechanical stretch TRPC2 ∼1–3 PLC activation, diacylglycerol (DAG) Abnormal sexual and mating behavior TRPC3 ∼1.5 PLC activation, store depletion, conforma- Defects in motor coordination and walking behavior tional coupling, DAG, exocytosis

TRPC4 ∼1–8 PLC activation, store depletion (?), PIP2 break- Impaired vascular function, altered 5-HT-mediated GABA down, exocytosis release, defects in intestinal motility TRPC5 ∼2–9 PLC activation, store depletion (?), Decreased anxiety-like behavior sphingosine-1-phosphate, exocytosis

TRPC6 ∼5 PLC activation, conformational coupling, DAG, Grossly normal, increased artery contractility, impaired light

PIP3 response in intrinsically photosensitive retinal ganglion cells in TRPC6/TRPC7 compound KO mice TRPC7 ∼1–5 PLC activation, store depletion, DAG Impaired light response in intrinsically photosensitive retinal ganglion cells in TRPC6/TRPC7 compound KO mice TRPV1 ∼4–10 Heat (43˚C), vanilloids, proinflammatory Reduced inflammatory hyperalgesia, impaired bladder

cytokines, protons, PIP2 function TRPV2 ∼1–3 Heat (52˚C), osmotic cell swelling, exocytosis Accelerated mortality in bacterial infection TRPV3 ∼1–10 Warm (33–39˚C); PUFAs; menthol; com- Impaired thermosensation, skin barrier effects, curved pounds from oregano, cloves, and thymes whiskers, and hair TRPV4 ∼6 Warm (27–34˚C), osmotic cell swelling, 5 Altered body osmolarity; increased bone mass; impaired 6-EET, anandamide, 4αPDD, exocytosis bladder function; reduced inflammatory hyperalgesia TRPV5 >100 Constitutively active1, exocytosis (?) Impaired renal Ca2+ reabsorption; decreased bone thickness TRPV6 >100 Constitutively active1, store depletion (?), exo- Impaired epididymal Ca2+ absorption, male hypofertility, cytosis (?) impaired Ca2+ absorption TRPM1 <1 Translocation (?) Impaired ON bipolar cell function and vision TRPM2 ∼0, 3–2 ADP-ribose, cADP-ribose, pyrimidine Impaired neutrophil infiltration in inflammation, increased ROS

nucleotides, arachidonic acid, NAD, H2O2, production in phagocytes Ca2+ TRPM3 ∼1–102 constitutively active1, osmotic cell swelling, Impaired noxious heat perception store depletion (?), d-erythro-sphingosine (?), pregnenolone sulfate

2+ TRPM4 Monovalent selective Ca , voltage modulated, PIP2 Increased release of inflammatory mediators from mast cell and cutaneous anaphylaxis; impaired dendritic cell migration; reduced secondary hemorrhage and lesions after spinal cord injury, hypertension associated with increased catecholamine release from chromaffin cells TRPM5 Monovalent selective Taste receptor activation (T1R, T2R), Ca2+, Impaired sweet, umami, and bitter taste reception; deflects

voltage modulated, PIP2, heat (15–35˚C) in glucose-induced insulin release TRPM6 <103 Mg2+ inhibited, translocation Embryonic lethality, neural tube defects in development TRPM7 ∼0.2–23 Activation mode of native channels unclear, Embryonic lethality; conditional TRPM7 deletion in T cells Mg2+ inhibited, ATP, protons, phosphoryla- causes abnormal thymocyte development

tion, PIP2 TRPM8 ∼0.3–4 Cool (23–28˚C), menthol, icilin, pH modulated, Deficiencies in response to cold

PIP2 TRPA1 ∼0.8–5 Cold (17˚C) (?), icilin, isothiocyanates, allicin Reduced response to noxious cold and intestine mechanical (garlic), cannabinoids, bradykinin, PLC activa- force tion, DAG, PUFAs

(Continued)

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Table 1 | Continued

Subtype Selectivity PCa2+/PNa+ Activation/modulation of activity Consequences ofTRP-deletion in mice

TRPML 1 4 Activation mode of native channels unclear, Motor deficits, retinal degeneration, decreased life span potentiation by low pH

TRPML 2 4 Activation mode of native channels unclear, – potentiation by low pH

TRPML 3 5 Activation mode of native channels unclear, Varitint-waddler (Va) mice with a TRPML3 (A419P) gain of removal, and readdition of extracellular Na+ function mutation exhibit deafness, circling behavior, and pigmentation defects TRPP2 Non-selective Translocation with TRPP1, fluid flow, mechan- Lethal E13; embryonic cysts and extrarenal abnormalities ical gating (?) including left-right asymmetry of visceral organs TRPP3 ∼1–10 Ca2+, voltage modulated – TRPP5 non-selective ? –

1Not yet measured in primary cells; 2significant differences in individual splice variants; 3divalent cation selective (Ca2+ and Mg2+); 4localization primarily intracellularly in endolysosomes, permeability for Na+,K+,Ca2+,Fe2+, for more details see Cheng et al. (2010); 5localization primarily intracellularly in endolysosomes, permeability for Na+,Ca2+,K+; for more details see Cheng et al. (2010). been identified, but one explanation is that at high expression lev- of TRPC4 leads to an 80% reduction of ACh-evoked currents + els the transfected TRPCs titrate regulatory subunits that confer which are predominantly carried by Na and activated by PIP2 SOCE characteristics to TRPCs. Although numerous studies show breakdown rather than by store depletion (Freichel et al., 2001; that Orai1 is the pore-forming subunit of store-operated channels Tsvilovskyy et al., 2009). These results show that TRPC gating and (Lewis, 2007), a model with Orai as a regulatory subunit of SOCE function cannot necessarily be extrapolated across cell types. channels composed of pore-forming TRPC subunits has recently TRPC3, TRPC6, and TRPC7 when expressed in heterologous been proposed (Liao et al., 2008). Additionally, Stim1 was found to systems are potentiated by Gq/11-coupled receptors or by direct hetermultimerize TRPC proteins either directly (TRPC1, TRPC4, application of diacylglycerol (DAG) analogs (Hofmann et al., TRPC5) or indirectly (TRPC3, TRPC6) to determine their store- 1999). Interestingly, the density of inward currents evoked by a operated activation mode (Yuan et al., 2007, 2009). Taken together, DAG derivate were significantly higher in smooth muscle cells iso- the question of whether and how TRPC proteins contribute to lated from Trpc6 −/− mice. This was explained by formation of SOCE remains highly controversial (Parekh, 2010) and cannot be TRPC3 homo-oligomeric channel complexes in TRPC6-deficient generally answered but may depend on the relative expression of smooth muscle cells, because mRNA expression of Trpc3 appears the above mentioned and/or not yet identified constituents that to be up-regulated two- to threefold in cells of Trpc6 −/− mice make up SOC channel complexes in individual cell types. (Dietrich et al., 2005). This example demonstrates that the analy- The permeability (PCa/PNa) of channels formed by heterolo- sis of cation channels consisting of TRPC proteins is further gously expressed TRPC proteins varies between 1 and 10 (Table 1 aggravated by the fact that inactivation of a given TRP protein and Venkatachalam and Montell, 2007; Gees et al., 2010). Whether may be compensated by up- or down-regulation of other genes TRPC1 can form functional homomeric channels by itself still including physically or functionally interacting TRP genes. Time- remains debatable. TRPC1 forms heteromeric channels with dependent inactivation strategies may be used in such cases, or TRPC4 or TRPC5, which have properties distinct from those of compound knock-out mice in which all redundant TRP proteins homomultimers (Strubing et al., 2001). TRPC4 and TRPC5 share are inactivated simultaneously. many structural and functional characteristics such as the acti- Trpc2 is a pseudogene in humans, but its rodent ortholog vation by Gq/11-coupled receptors. On the other hand there are encodes a functional TRPC2 channel important to pheromone considerable discrepancies regarding the precise activation mech- sensing in vomeronasal organ, where it can be directly activated anism in response to PLC stimulation and with respect to their by DAG (Lucas et al., 2003). channel properties (e.g., permeability), even if homomeric TRPC Expression of Trpc genes was found in various types of mast proteins are analyzed (Cavalie, 2007). The differences may result cells (Table 2). TRPC1 has been detected in murine BMMC on from the expression system used and thereby emphasize the need mRNA (Sanchez-Miranda et al., 2010; Suzuki et al., 2010) and to analyze the action of individual TRPC proteins in the context protein (Hernandez-Hansen et al., 2004) level, also in the rat cell of their native environment. This can be exemplified by studies line RBL-2H3 (Ma et al., 2008) and using a microarray expression in mice with inactivation of the Trpc4 gene. Depending on the analysis in human skin mast cells (Bradding et al., 2003). In RBL- cell type studied, channels with completely different characteris- 2H3 cells, knockdown of TRPC1 and TRPC3 proteins through tics are impaired in Trpc4 -deficient mice: deletion of the Trpc4 expression of corresponding shRNAs decreased the cells sensitiv- gene results in 95% reduction of acetylcholine (ACh)-triggered ity to antigen-stimulation and shifted the Ca2+ wave initiation store-operated channels with a Ca2+ over Na+ selectivity of >100 site from the tips of extended cell protrusions to the cell body in endothelial cells whereas in ileal smooth muscle cells the loss (Cohen et al., 2009). Interestingly, in mice deficient for the Src

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Table 2 | Expression ofTRP transcripts and proteins in mast cell models.

Species Cell type Name Method Reference

TRPC1 Mouse Primary cells BMMC qRT-PCR Suzuki et al. (2010) Mouse Primary cells BMMC RT-PCR Sanchez-Miranda et al. (2010) Rat Cell line RBL-2H3 RT-PCR,WB Ma et al. (2008) Mouse Primary cells BMMC WB Hernandez-Hansen et al. (2004) Human Primary cells skin mast cells Affymetrix gene array Bradding et al. (2003) TRPC2 Rat Cell line RBL-2H3 RT-PCR Ma et al. (2008) TRPC3 Mouse Primary cells BMMC RT-PCR Sanchez-Miranda et al. (2010) Mouse Primary cells L138.8A qRT-PCR Sel et al. (2008) Rat Cell line RBL-2H3 RT-PCR,WB Ma et al. (2008) Mouse Primary cells BMMC WB Hernandez-Hansen et al. (2004) TRPC4 Mouse Primary cells BMMC qRT-PCR Suzuki et al. (2010) Mouse Primary cells BMMC WB Hernandez-Hansen et al. (2004) TRPC5 Mouse Primary cells BMMC qRT-PCR Suzuki et al. (2010) Mouse Primary cells BMMC RT-PCR Sanchez-Miranda et al. (2010) Rat Cell line RBL-2H3 RT-PCR,WB Ma et al. (2008) TRPC6 Mouse Primary cells BMMC RT-PCR Sanchez-Miranda et al. (2010) Mouse Primary cells BMMC WB Hernandez-Hansen et al. (2004) Mouse Cell line PB-3c NB Buess et al. (1999) TRPC7 Rat Cell line RBL-2H3 RT-PCR Ma et al. (2008) Mouse Primary cells BMMC IP Sanchez-Miranda et al. (2010) TRPV1 Human Cell line HMC-1 WB, RT-PCR Zhang et al. (2011) Human Mast cells in bladder IHC Lazzeri et al. (2004) Rat Cell line RBL-2H3 RT-PCR Stokes et al. (2004) Human Skin mast cells IHC Stander et al. (2004) TRPV2 Human Cell line HMC-1 WB, RT-PCR Zhang et al. (2011) Human Cell line HMC-1 RT-PCR Kim et al. (2010) Rat Cell line RBL-2H3 RT-PCR, NB, WB, ICC, qPCR Stokes et al. (2004) Mouse Cell line P815 NB, WB Stokes et al. (2004) Mouse Primary cells BMMC WB, (qPCR) Stokes et al. (2004) Rat Cell line RBL-2H3 NB, WB, ICC Stokes et al. (2005) Mouse Cell line P815 NB, WB Stokes et al. (2005) Human Primary cells HLMC Affymetrix gene array Bradding et al. (2003) Human Primary cells Skin mast cells Affymetrix gene array Bradding et al. (2003) Human Primary cells CBMC Affymetrix gene array Bradding et al. (2003) TRPV3 Not reported TRPV4 Human Cell line HMC-1 WB, RT-PCR Zhang et al. (2011) Human Cell line HMC-1 RT-PCR Kim et al. (2010) Rat Cell line RBL-2H3 ICC Yang et al. (2007) Rat Cell line RBL-2H3 RT-PCR Stokes et al. (2004) TRPV5 Not reported

(Continued)

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Table 2 | Continued

Species Cell type Name Method Reference

TRPV6 Rat Cell line RBL-2H3 RT-PCR Stokes et al. (2004) TRPM1 Not reported TRPM2 Human Primary cells HLMC Affymetrix gene array Bradding et al. (2003) Human Primary cells CBMC Affymetrix gene array Bradding et al. (2003) TRPM3 Not reported TRPM4 Mouse Primary cells BMMC RT-PCR, NB, WB, ICC Vennekens et al. (2007) TRPM5 Not reported TRPM6 Not reported TRPM7 Rat Cell line RBL-2H3 RT-PCR Stokes et al. (2004) Human Primary cells HLMC RT-PCR Wykes et al. (2007) Human Cell line HMC-1 RT-PCR Wykes et al. (2007) Human Cell line LAD-2 cells RT-PCR Wykes et al. (2007) TRPM8 Mouse Primary cells BMMC RT-PCR Medic et al. (2011) Rat Cell line RBL-2H3 RT-PCR, ICC Cho et al. (2010) TRPA1 Rat Cell line RBL-2H3 ICC, WB Prasad et al. (2008) TRPP1 Not reported TRPP2 Not reported TRPP3 Not reported TRPML1 Not reported TRPML2 Not reported TRPML3 Not reported

BMMC, bone marrow-derived mast cells; CMBC, cord blood derived mast cells; HLMC, human lung mast cells; ICC, immunocytochemistry; IHC, immunohistochem- istry; IP,Immunoprecipitation; NB, Northern blot; (q)RT-PCR, (quantitative) reverse transcriptase polymerase chain reaction; WB, Western blot. family kinase Fyn expression of TRPC1 proteins was reduced by 2008). In BMMCs, transcripts of Trpc4 and Trpc5 (Suzuki et al., ∼30%, and cation currents, depolymerization of cortical F-actin 2010) and TRPC4 proteins (Hernandez-Hansen et al., 2004)were and degranulation triggered by FcεRI-stimulation was signifi- found. TRPC5 transcript and protein expression was reported in cantly reduced whereas mast cell degranulation evoked by ATP, RBL-2H3 cells (Ma et al., 2008). shRNA-mediated knock down of substance P, or thrombin was unaffected. Similar effects were TRPC5 in RBL-2H3 cells was associated with a reduced Ca2+ entry observed by downregulation of TRPC1 expression using siR- following depletion of intracellular Ca2+ stores and based on over- NAs against TRPC1 and the deficits in FcεRI-triggered mast cell expression experiments in these cells it was proposed that TRPC5 activation could be rescued by exogenous expression of TRPC1 associates with Stim1 and Orai1 in a stoichiometric manner to (Suzuki et al., 2010). Trpc2 mRNA has been reported in mouse build Ca2+ and Sr2+ permeable channels that can be discriminated BMMC using RT-PCR (Ma et al., 2008). Expression of TRPC3 was from channels made by Orai1 and Stim1 (Ma et al., 2008). How- reported in mouse BMMC via Western Blot (Hernandez-Hansen ever, receptor-mediated Ca2+ entry or membrane currents have et al., 2004) and RT-PCR (Sanchez-Miranda et al., 2010) and with not been analysed in this study. Trpc6 and Trpc7 transcripts and both methods in the cell lines L138.8A and RBL-2H3 (Ma et al., proteins were also found in mouse BMMC (Hernandez-Hansen

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et al., 2004; Sanchez-Miranda et al., 2010) and based on immuno- thermosensitive TRP channels. Since ruthenium red inhibited the 2+ precipitation experiments using an antibody that was designed to elevation of [Ca ]i and subsequent histamine release in RBL-2H3 detect all three members of the TRPC3/TRPC6/TRPC7 subfamily cells induced by shear stress (Yang et al., 2009) and temperature it was proposed that TRPC3/TRPC6/TRPC7, like TRPC1 (Suzuki increase (Stokes et al., 2004) or after irradiation with soft power et al., 2010), interact with fyn kinase during FcεRI-mediated mast lasers (Yang et al., 2007), a role of TRPV proteins was proposed cell activation (Sanchez-Miranda et al., 2010). in the above mast cell activating pathways. As Ruthenium Red inhibits several other channels in addition to TRPV channels, this TRPV CHANNELS concept requires validation by independent approaches. + Similar to the TRPC family, the TRPV (vanilloid) family can Transcripts of Trpv6 (formerly designated as Ca2 transport be divided into two subfamilies on the basis of structure, func- protein 1,CaT1) have been detected in RBL-2H3 cells (Stokes et al., tion and Ca2+ selectivity: TRPV1-4, and TRPV5/6. In the TRPV 2004). It had been proposed that TRPV6 comprises all or part of subfamily, TRPV5 and TRPV6 can form heteromeric channel the CRAC pore (Yue et al., 2001) but later it was shown that TRPV6 complexes (Hoenderop et al., 2003b; Hellwig et al., 2005; Schae- expressed in HEK cells and CRAC in RBL-2H3 cells exhibit many fer, 2005). Furthermore, TRPV1 can associate with TRPV2 and differences in biophysical properties demonstrating that the pores TRPV3 (Cheng et al., 2007) and widespread interaction has been of TRPV6 and CRAC are not identical (Voets et al., 2001). In this shown for TRPV1-TRPV4 (Cheng et al., 2007). line, treatment of RBL-2H3 cells with antisense and siRNA probes TRPV1, TRPV2, TRPV3, and TRPV4 are non-selective cation directed against Trpv6 transcripts, respectively, does not affect channels that are activated by a different range in temperatures, endogenous CRAC currents corroborating that TRPV6 is not a respectively, and by numerous other stimuli (Table 1). In addition, component of the native CRAC current in RBL mast cells. Nev- TRPV1 could be activated by low pH (Caterina et al., 1997; Jordt ertheless, expression of amino-terminal TRPV6 fragments, which et al., 2000) and by vanilloid compounds, such as capsaicin and are able to suppress currents through over-expressed TRPV6 chan- capsinate found in hot (chili) and non-pungent (bell) peppers, nels, substantially suppressed activation of endogenous CRAC respectively (Caterina et al., 1997; Iida et al., 2003). (Kahr et al., 2004). TRPV2 (like TRPV4) is activated by osmotic cell swelling and has a critical role in macrophage particle binding and phago- TRPM CHANNELS cytosis (Link et al., 2010). TRPV3 is activated by a variety of The members of the TRPM (melastatin) family are divided into botanical compounds (Moqrich et al., 2005). TRPV4 is sensi- four groups: TRPM1/3, TRPM2/8, TRPM4/5, and TRPM 6/7. tive to osmotic and mechanical stimuli, such as cell swelling or For TRPM channels, heteromerization has only been reported for fluid flow. It could be activated by arachidonic acid metabolite 5, TRPM6 and TRPM7 so far (Chubanov et al., 2004, 2005; Li et al., 6-epoxyeicosatrienoic acid (5,6-EET; Vriens et al., 2005)orby 2006; Jiang, 2007). The Ca2+ permeability of channels formed 4α-Phorbol 12,13-Didecanoate (Watanabe et al., 2002). by TRPM proteins ranges from monovalent selective (TRPM4 TRPV5 and TRPV6 are the only highly Ca2+-selective chan- and TRPM5) to highly Ca2+ permeable (TRPM3α2, TRPM6, and nels in the TRP channel family. They are not heat-sensitive and TRPM7). 2+ tend to be active at low [Ca ]i concentrations and physiologi- The founding member of this subfamily, Trpm1 (initially cal membrane potentials (Vennekens et al., 2000). Both proteins termed melastatin), was initially identified as a gene that is down- form constitutively active channels when heterologously expressed regulated in highly metastatic melanoma cells (Duncan et al., in different cell lines, but similar channel activity has never been 1998). TRPM1 proteins reside in intracellular organelles and do recorded in the primary cell types that express TRPV5 or TRPV6, not reach the plasma membrane upon heterologous expression, respectively. TRPV5 is essential for Ca2+ reabsorption in the but form non-selective currents when expressed in SK-Mel22a kidney (Hoenderop et al., 2003a), and TRPV6 proteins deter- melanoma cells (Oancea et al., 2009). TRPM1 is activated by the mine Ca2+-absorption in the epididymal epithelium and, thereby, mGluR6 signaling cascade and thus is required for the depolarizing sperm function and male fertility (Weissgerber et al., 2011). light response in ON bipolar cells (Morgans et al., 2009) and muta- All members of the TRPV proteins were reported to be tionsintheTrpm1 gene are associated with congenital stationary expressed in various mast cell models except TRPV3 and TRPV5. night blindness (CSNB) disease in humans (Li et al., 2009). For example, transcripts of Trpv1, Trpv2, Trpv4, and Trpv6 were TRPM3 proteins are able to form constitutively active cation identified in RBL-2H3 cells (Stokes et al., 2004), Trpv1, Trpv2, and channels. Various splice variants are expressed from the Trpm3 Trpv6 in the human cell line HMC-1 (Zhang et al., 2011) and gene with TRPM3α1 being poorly permeable for divalent cations, TRPV1 proteins in mast cells of the human bladder (Lazzeri et al., whereas TRPM3α2-induced channels conduct Ca2+ and Mg2+. 2004) and skin (Stander et al., 2004). The TRPV1 specific ago- The steroid hormone pregnenolone sulfate may act as endogenous nists capsaicin or resiniferatoxin induced calcium uptake in several ligand for TRPM3 (Wagner et al., 2008). mouse mast cell lines,in BMMC,but not in PMC (Biro et al.,1998). TRPM2 is activated by ADP-ribose (EC50, 100 μM) and acti- Treatment of BMMCs with ruthenium red, that is used as vatedbyH2O2 and under conditions of ROS production (Hara non-specific inhibitor of TRPV channels (Vriens et al., 2009), et al., 2002; Perraud et al., 2005), and deletion of Trpm2 leads inhibited FcεeRI-mediated increase of cytosolic Ca2+ concen- to decreased reactive oxygen species-induced chemokine produc- tration (Lam et al., 2008). Mast cells are not only activated by tion in monocytes (Yamamoto et al., 2008). Recently, Di et al. specific allergens but also by various physical stimuli, e.g., rub- (2011) showed that deletion of Trpm2 increases ROS production bing, pressure, cold, heat which induce physical urticaria (Grabbe, in phagocytes and introduced the concept that TRPM2-mediated 2001). These processes might be mediated through mechano- or cation entry and subsequent membrane depolarization functions

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as an inhibitory feedback mechanism for ROS production in these antigen-induced mast cell activation (Vennekens et al., 2007). cells. Additionally, antigen- and SCF-induced migration of BMMCs is TRPM4 and TRPM5 are (together with TRPM3α1) the only largely diminished in the absence of TRPM4, and F-actin forma- monovalent-selective ion channels of the TRP family (Launay tion is reduced in DNP-HSA-stimulated BMMCs from Trpm4 −/− et al., 2002; Hofmann et al., 2003). TRPM4, but not TRPM5, is mice (Shimizu et al.,2009).At this point it has to be mentioned that 2+ inhibited by intracellular ATP, whereas TRPM5 is inhibited by the increased [Ca ]i elevation observed upon FcεRI-stimulation intracellular acidic pH. Both are activated by an increase in Ca2+ in TRPM4-deficient mice led to increased release of TNF-α but 2+ levels in the cytosol, but the sensitivity to [Ca ]i as determined not of IL-6. It is known, that release of both mast cell mediators by different research groups varies greatly (Vennekens and Nil- is calcium-dependent, but an explanation for this difference may ius, 2007). Studies in Trpm4 −/− mice reveal a critical role for be that transcription and/or production of IL-6 may already be TRPM4 proteins in mast cell activation (see below). Moreover, saturated under these conditions of FcεRI-stimulation and could 2+ these mice exhibited high blood pressure due to elevated release of not be further stimulated by the additional increase of [Ca ]i in catecholamines (Mathar et al., 2010). Trpm5 −/− mice show abol- TRPM4-deficient BMMCs. ished sweet, umami, and bitter taste reception (Zhang et al., 2003) Expression of TRPM7 has been found in human lung mast cells and impaired glucose-induced insulin secretion (Colsoul et al., and the human cell line LAD-2 (Wykes et al., 2007)aswellasin 2010). RBL-2H3 cells (Stokes et al., 2004) and Mg2+-inhibited currents TRPM6 and TRPM7 are unique among ion channels because (MIC), which can be mediated by TRPM7 proteins, were identi- they possess both ion channel and protein kinase activities. Chan- fied in RBL-2H3 cells, HMC-1 cells, and human lung mast cells. nels formed by these proteins allow Mg2+ and Ca2+ entry into the Downregulation of TRPM7 expression in HMC-1 cells and human cell and are inhibited by intracellular Mg2+ (0.3–1.0 mM; Nadler lung mast cells resulted in significant reduction of MIC currents et al., 2001; Voets et al., 2004b). TRPM6 is primarily expressed in and mast cell survival which could not be rescued by an increase kidney and intestine, where it has been suggested to be responsi- in the extracellular Mg2+ concentration (Wykes et al., 2007). In ble for epithelial Mg2+ reabsorption (Schlingmann et al., 2002). addition, TRPM7 currents in RBL-2H3 cells might be involved in TRPM7 is ubiquitously expressed and deletion of the Trpm7 gene Ca2+ and Mg2+ entry during cell cycle regulation since it could be leads to embryonic lethality (Jin et al., 2008; Weissgerber et al., shown that MIC currents were strongly upregulated specifically in 2008). the G1 phase of the cell cycle to meet cellular demands for Ca2+ Like TRPM1, TRPM8 was originally identified in a screen of and/or Mg2+ fluxes during this stage of cell division (Tani et al., cancer-related genes (Tsavaler et al., 2001). It can be activated by 2007). Trpm7 -deficient mice as well as mice homozygous for an cold (8–28˚C) and enhanced by cooling compounds such as men- allele lacking the kinase domain of TRPM7 (Trpm7 Δkinase/Δkinase ) thol and icilin (McKemy et al., 2002) and Trpm8 −/− mice show die early during development (Jin et al., 2008; Weissgerber et al., deficits in their ability to discriminate between cold and warm 2008; Ryazanova et al., 2010), but Trpm7 +/Δkinase are viable and surfaces (Bautista et al., 2007). Temperature modulates the voltage MIC currents are significantly reduced in PMCs of these mice dependence of the channel, and menthol and icilin mimick this (Ryazanova et al., 2010). However, the consequences of MIC cur- effect (Voets et al., 2004a). rent reduction for mast cell activation have not been reported so Expression of TRPM1, TRPM3, TRPM5, and TRPM6 has not far. been reported in mast cell models, while the other members of TRPM8 proteins, which form Ca2+-conducting cation chan- TRPM subfamily play important roles in mast cell functions. nels activated by menthol or cold, have also been proposed as Trpm2 transcripts were identified in human lung mast cells and mediators of mast cell activation, e.g., in the development of cold cord blood derived mast cells in a microarray expression analysis urticaria. However, Medic et al. (2011) found no deficits in mast (Bradding et al., 2003). In mouse BMMC, Trpm4 transcripts were cell activation using Ca2+ imaging, mast cell degranulation and detected using Northern blot analysis and the 138 kDa TRPM4 development of passive anaphylaxis in Trpm8 −/− mice, which proteins were identified in BMMCs of wild type but not of makes a role of TRPM8 for mast cell activation in cold urticaria Trpm4 −/− mice (Vennekens et al., 2007). After preabsorbtion of unlikely. the same anti-TRPM4 antibody using microsomal membrane pro- − − tein fractions from BMMCs of TRPM4 / mice a specific staining TRPA1 CHANNELS of TRPM4 proteins in connective tissue mast cells in skin sections TRPA1 is the only member of the TRPA (ankyrin) family char- could be achieved. TRPM4 proteins, similarly like TRPM5 pro- acterized by the 14 amino-terminal ankyrin repeats (Story et al., teins, act as Ca2+-activated non-selective cation channels and crit- 2003). Its expression in hair cells led to the hypothesis that it ically determine the driving force for Ca2+ influx into cells (Launay forms an auditory mechanotransduction channel (Corey et al., et al., 2004). It could be shown that TRPM4 channels depolar- 2004), but this concept could not be supported sufficiently as, ize the membrane following adenosine- and FcεRI-stimulation e.g., Trpa1−/− mice exhibit no overt vestibular deficits and audi- and, thereby, critically decrease the Ca2+ influx in BMMC’s via tory responses are completely normal (Bautista et al., 2006; Kwan CRAC channels. Accordingly, activated Trpm4 −/− BMMCs release et al., 2006). TRPA1 was reported to be activated by noxious excessive histamine,leukotrienes and tumor necrosis factor (TNF), cold but the thermosensitivity (Story et al., 2003; Corey et al., and Trpm4 −/− animals display a more severe acute anaphylactic 2004) of TRPA1 is also debated. TRPA1 is activated by vari- response in the skin compared to wild-type controls indicating that ous chemicals (Bandell et al., 2004) including allyl isothiocyanate TRPM4 channel activation is an efficient mechanism for limiting (the pungent compound in mustard oil), allicin (from garlic),

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cinnamaldehyde (from cinnamon), menthol (from mint), tetrahy- has been described (Ma et al.,2010). It has to be mentioned that the drocannabinol (from marijuana), nicotine (from tobacco), and nomenclature of TRPP proteins was changed recently (Clapham bradykinin (see Table 1). Recently it was reported that pro- et al., 2012), and TRPP2 is now designated TRPP1, TRPP3 is now tein kinase A/phospholipase C-mediated trafficking to the plasma TRPP2, and TRPP5 is now TRPP3. Until now, members of the membrane contributes to TRPA1 activation (Schmidt et al., 2009). TRPML- or TRPP-channel subfamily were not identified in mast TRPA1 has been detected in mast cells so far, but in resting mast cells. cells it was predominantly localized in intracellular vesicular struc- tures and interacts with secretogranin III, a protein involved in MECHANISMS: HOW TRP CHANNELS REGULATE CHANGES 2+ secretory granule biogenesis in mast cells, implicating that TRPA1 IN [CA ]i AND MAST CELL ACTIVATION might play an alternative role to the regulation of cation entry Taken together, TRP channels were found to influence cellular across the plasma membrane in mast cells compared to other cell Ca2+ signaling by several mechanisms. First, by conducting Ca2+ types (Turner et al., 2007; Prasad et al., 2008). ions to various degrees TRP channels directly contribute to Ca2+ influx via the plasma membrane. TRP channels with high cal- TRPML AND TRPP CHANNELS cium selectivity are TRPV5 and TRPV6 (Vennekens et al., 2000), The TRPML (mucolipin) family contains three mammalian mem- but also non-selective TRP channels composed of, e.g., TRPC1 bers: TRPML1, TRPML2, and TRPML3. The TRPML proteins (Suzuki et al., 2010) or TRPC5 (Ma et al., 2008)maycontributein show only low homology with the other TRP channels and are this way. Second, by conducting Na+ TRP channels mediate elec- comparatively shorter. Heterologously expressed TRPML pro- trogenic effects through plasma membrane depolarization which teins can interact with each other (Venkatachalam et al., 2006; may have opposite consequence in different cell types: in contrast Curcio-Morelli et al., 2010). Trpml1 was first identified by a posi- to excitable cells, where TRP-mediated Na+ entry and depolar- tional cloning strategy as the gene mutated in patients suffering ization can enhance Ca2+ entry by gating of voltage-operated from Mucolipidosis type IV (MLIV; Bargal et al., 2000), TRPML3 Ca2+ channels (Tsvilovskyy et al., 2009), they can do the oppo- was discovered as the channel mutated in varitint-waddler mice, site in non-excitable cells such as mast cells; here a significant characterized by a variegated coat color, vestibular defects, hyper- part of stimulated Ca2+ entry enters the cell via inwardly rec- activity, and embryonic lethality (Xu et al., 2007). TRPML1 and tifying CRAC channels, and TRP-mediated Na+ entry and sub- TRPML2 are ubiquitously expressed and localize primarily to the sequent depolarization reduces the driving force for Ca2+ entry lysosomal and late endosomal compartments (Manzoni et al., by shifting the membrane potential toward more positive poten- 2004; Puertollano and Kiselyov, 2009). Recently, Dong et al. devel- tials (Vennekens et al., 2007). A counteracting mechanism by oped a method allowing the measurement of ion currents directly aCa2+ activated K+ channel leading to membrane hyperpo- in endolysosomes. This was achieved by treatment of the cells with larization and an increase of the driving force for Ca2+ entry Vacuolin-1, leading to an increase of diameter of the endolyso- following FcεRI-stimulation was shown for SK4 (KCa3.1) pro- somes from 0.1–0.5 to 2–3 μM which makes them accessible teins (Shumilina et al., 2008) emphasizing the relevance of this 2+ for patch-clamp measurements. In this way, it could be shown regulatory principle for adjusting [Ca ]i and activation of mast that expressed TRPML1 proteins form constitutively active cation cells. Third, TRP channels can be activated or inhibited by them- channels which, besides Na+ and Ca2+, can conduct several other selves by Ca2+ which further contributes to the complexity of 2+ 2+ 2+ 2+ 2+ cations, e.g., Mn ,Zn , and Fe out of the lumen of the regulation of [Ca ]i. TRP channels that are activated by Ca organelles into the cytosol. The mechanism leading to activation include TRPC1,TRPC4,TRPC5,TRPC6,TRPV4,TRPM2,TRPA1, of TRPML1 is still unclear (Dong et al., 2008, 2010). TRPM4, and TRPM5. Also many TRP channels are modulated by The TRPP (polycystin) family comprises eight members, from Ca2+ via complex signaling cascades including Ca2+/calmodulin which only PKD2 (TRPP2, PC2, polycystin-2), PKD2-L1 (TRPP3, binding, Ca2+-dependent modulation of phospholipase C, and polycystin-L), and PKD2-L2 (TRPP5, polycystin-L2) are shown to Ca2+-dependent activation of PKC. Fourth, there is emerging be channels. TRPP2 is reported to form a Ca2+-permeable cation evidence that several TRP channels are also located in the mem- channel in the plasma membrane that can be activated by down- brane of the sarco/endoplasmic reticulum (SR/ER), endosomes, stream of G protein-coupled receptor and/or receptor-tyrosine lysosomes, or other intracellular vesicles where they can serve as kinase at the cell (Ma et al., 2005), but was also shown to form Ca2+ release channels and conduct Ca2+ from the luminal stores aCa2+ release channel in the ER (Wegierski et al., 2009). TRPP3 into the cytoplasm which may affect specific mast cell functions; is reported to form Ca2+-permeable non-selective cation chan- for instance, it was reported that TRPV1, TRPM8, and TRPP2 nels with a large single channel conductance modulated by pH can form Ca2+-conducting channels in the SR/ER, and TRPML1, (Chen et al., 1999; Huang et al., 2006). TRPP5 is thought to form TRPM2, and TRPV2 may function as Ca2+-release channels in aCa2+-permeable non-selective cation channel (Guo et al., 2000). endo-/lysosomes (for more details see Dong et al., 2010; Gees et al., As indicated above, individual members of TRP subfamilies are 2010). Finally, it has to be considered that many studies about able to interact. However, TRPP2 was the first example showing Ca2+-dependent mast cell functions analysed measurements of that heteromultimerization cannot only occur between members global cytoplasmic Ca2+ concentration rather than the nature of of the same subfamily since interaction of TRPP2 was reported the Ca2+ signals, e.g., differences in the frequency of transient with TRPC1 (Tsiokas et al., 1999; Bai et al., 2008; Kobori et al., episodic Ca2+ elevations (Ca2+ spikes/oscillations) and subcellu- 2009; Zhang et al., 2009) or with TRPV4 (Kottgen et al., 2008; lar localization and direction of Ca2+ signals such as Ca2+ waves Stewart et al., 2010). Recently, also another example of interaction which may be crucial for distinct mast cell functions. In this line, of TRP proteins of different subfamilies, i.e., TRPV4 with TRPC1, a threshold of Ca2+ elevation in the vicinity of store-operated

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Ca2+ channels is apparently necessary to induce nuclear NFAT specific pattern of mast cell activation such as activation of indi- translocation as a parameter for activation of gene expression (Kar vidual transcription factors or release of a defined set of mast cell et al., 2011, 2012). In this case the signal triggered by this localized mediators. Ca2+ entry pathway might be achieved by spatially sequestered calmodulin molecules as mediators. Likewise, it would not be sur- ACKNOWLEDGMENTS prising if also a specific localization pattern of certain TRP channel This work was supported by the Deutsche Forschungsgemein- proteins and their dynamic change during mast cell activation schaft including the Schwerpunktprogramm 1394 (“Mast cells – could be identified in the future as a mechanism that explains a promotors of health and modulators of disease,”SPP 1394).

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Early embryonic lethal- vates inflammatory neutrophil infil- cell degranulation induced by phys- This article was submitted to Frontiers in ity following inactivation of the tration. Nat. Med. 14, 738–747. ical stimuli involves the activa- Molecular Innate Immunity, a specialty TRPM7 gene in mice. Naunyn Yang, W., Chen, J., and Zhou, L. (2009). tion of transient-receptor-potential of Frontiers in Immunology. Schmiedebergs Arch. Pharmacol. Effects of shear stress on intracel- channel TRPV2. Physiol. Res. 61, Copyright © 2012 Freichel, Almering 377, 35. lular calcium change and histamine 113–124. and Tsvilovskyy. This is an open-access Weissgerber, P., Kriebs, U., Tsvilovskyy, release in rat basophilic leukemia Zhang, P., Luo, Y., Chasan, B., article distributed under the terms of V., Olausson, J., Kretz, O., Stoerger, (RBL-2H3) cells. J. Environ. Pathol. Gonzalez-Perrett, S., Montal- the Creative Commons Attribution Non C., Vennekens, R., Wissenbach, U., Toxicol. Oncol. 28, 223–230. betti, N., Timpanaro, G. A., Cantero Commercial License, which permits non- Middendorff, R., Flockerzi, V., and Yang, W. Z., Chen, J. Y., Yu, J. T., Mdel, R., Ramos, A. J., Goldmann, commercial use, distribution, and repro- Freichel, M. (2011). Male fertility and Zhou, L. W. (2007). Effects W. H., Zhou, J., and Cantiello, duction in other forums, provided the depends on Ca(2)+ absorption by of low power laser irradiation on H. F. (2009). The multimeric original authors and source are credited.

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