JOURNAL OF NEUROCHEMISTRY | 2010 | 113 | 313–328 doi: 10.1111/j.1471-4159.2010.06626.x The Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA Abstract potential (TRP) proteins are a superfamily (28 members in Ion channels are classically understood to regulate the flux of mammal) of Ca2+-permeable channels with diverse tissue ions across the plasma membrane in response to a variety of distribution, subcellular localization, and physiological func- environmental and intracellular cues. Ion channels serve a tions. Almost all mammalian TRP channels studied thus far, number of functions in intracellular membranes as well. These like their ancestor yeast TRP channel (TRPY1) that localizes channels may be temporarily localized to intracellular mem- to the vacuole compartment, are also (in addition to their branes as a function of their biosynthetic or secretory path- plasma membrane localization) found to be localized to ways, i.e., en route to their destination location. Intracellular intracellular membranes. Accumulated evidence suggests membrane ion channels may also be located in the endocytic that intracellularly-localized TRP channels actively participate pathways, either being recycled back to the plasma mem- in regulating membrane traffic, signal transduction, and brane or targeted to the lysosome for degradation. Several vesicular ion homeostasis. This review aims to provide a channels do participate in intracellular signal transduction; the summary of these recent works. The discussion will also be most well known example is the inositol 1,4,5-trisphosphate extended to the basic membrane and electrical properties of receptor (IP3R) in the endoplasmic reticulum. Some organellar the TRP-residing compartments. intracellular membrane channels are required for the ionic Keywords: endosomes, intracellular channel, lysosomes, homeostasis of their residing organelles. Several newly-dis- membrane traffic, TRP channel, TRPML. covered intracellular membrane Ca2+ channels actually play J. Neurochem. (2010) 113, 313–328. active roles in membrane trafficking. Transient receptor TRPs) are activated by a variety of environmental cues such TRP channels and organelles as temperature, mechanical force, and plant-derived volatiles (reviewed in Refs. Clapham 2003; Montell 2005; Nilius Overview of TRP channels et al. 2007). Many of the sensory TRPs, along with the Transient receptor potential (TRP) is a cation channel superfamily with diverse physiological functions including thermosensation and mechanosensation (excellently re- Received January 17, 2010; accepted January 25, 2010. Address correspondence and reprint requests to Haoxing Xu, The viewed in Refs. Clapham 2003; Montell 2005; Nilius et al. Department of Molecular, Cellular, and Developmental Biology, Uni- 2007). Mammalian TRPs can be divided into six subfamilies: versity of Michigan, 3089 Natural Science Building (Kraus), 830 North TRPC(1–7), TRPV(1–6), TRPM(1–8), TRPA(1), TRPP(1– University, Ann Arbor, MI 48109, USA. E-mail: [email protected] 3), and TRPML(1–3) (Fig. 1). In past years, extensive efforts Abbreviations used: AM, acetoxymethyl; BAPTA, 1,2-bis(2-amino- have been made to elucidate three basic aspects of TRP phenoxy)ethane-N,N,N¢,N¢-tetraacetic acid; CaM, Calmodulin; CICR, Ca2+-induced Ca2+ release; EPSP, excitatory postsynaptic potential; ER, channels: the channel pore properties, the activation (gating) endoplasmic reticulum; IP3R, inositol 1,4,5-trisphosphate receptor; LEL, mechanisms, and the channels’ subcellular localization. Of late endosomal and lysosomal; LROs, lysosome-related organelles; these, the biophysical properties of the TRP channel pore MHCII, major histocompatibility complex II; ML4, type IV mucolipi- have been best characterized. When activated, most TRPs dosis; NAADP, nicotinic acid adenine dinucleotide phosphate; PIP, conduct Ca2+, as well as Na+ and K+ ions. The activation/ phosphoinositide; PM, plasma membrane; RyR, ryanodine receptor; SG, secretory granule; SNARE, soluble NSF attachment protein receptors; gating mechanisms, however, have not been described in SR, sarcoplasmic reticulum; SV, secretory vesicle; SyV, synaptic vesicle; detail for most TRPs. In sensory cells such as somatosensory TG, thapsigargin; TGN, trans-Golgi network; TRP, transient receptor neurons, a subset of TRP channels (so-called ‘sensory’ potential. Ó 2010 The Authors Journal Compilation Ó 2010 International Society for Neurochemistry, J. Neurochem. (2010) 113, 313–328 313 314 | X.-P. Dong et al. C2 C7 C6 A1(Icilin) C3 V V V1(H+ ?, Capsaicin) C5 G V2 C4 ER or G ([Cl - ] , H+ ) V V lumen SV/SG EE V4 (Osmolarity ) C1 ? Fig. 1 Intracellular location and putative V3 activation mechanisms of TRP channels. TRPs can be divided into six groups V5 (TRPC, TRPV, TRPM, TRPA, TRPML, and RE TRPP). TRPML1-3, TRPV2, and TRPY1 M5 V6 (yeast TRP yvc1), and TRPM7 (in red) are likely to play active roles in membrane M4 traffic and exocytosis. TRPM2, TRPM8, ER ER TRPV1, TRPP1, TRPA1, and TRPV4 (in M8 LEL LEL 2+ P1([Ca ] i) (Cold/menthol) green) have been shown to be active in M2 V intracellular membranes and may play roles (ADPR, NAADP?) P2 SyV LY in intracellular signal transduction. TRPC3- P3 M7 V 6, TRPMV5/6, TRPM1, TRPM7, and EE TRPML2/3 (in blue) have been shown to M6 RE M3 M1 ML1 undergo regulated exocytosis. Intracellular ML3 Y1 ML2 localization of other TRPs (in black) has not (Mechanical force, [Ca 2+ ] ) i been well documented. non-sensory TRPs, are also expressed in non-sensory tissues. Ramsey et al. 2006). It is not known if vesicular intracellular Here the endogenous cellular cues activating the TRPs are membrane TRPs are modulated by these same signaling largely unknown, although ligands of the G protein-coupled molecules. It is also not known whether intracellular receptor and RTK (receptor tyrosine kinase) families report- membrane TRPs are modulated by luminal factors. Given edly activate or modulate TRPs in heterologous systems that the chemicophysical properties of intracellular mem- (reviewed in Ref. Ramsey et al. 2006). Initially thought to be branes differ significantly from those of the plasma mem- solely plasma membrane (PM) channels mediating Ca2+ brane (Watson and Pessin 2001), it is of interest whether entry, almost all mammalian TRPs studied thus far have also vesicular TRPs function in the secretory/endocytic pathways been found to be localized to intracellular vesicular mem- in a similar fashion to their plasma membrane counterparts. branes (Turner et al. 2003; Bezzerides et al. 2004; Krapi- In this review, we will mainly discuss TRP channels whose vinsky et al. 2006; Dong et al. 2008; Lange et al. 2009). residing compartments have been reasonably defined, espe- Despite the fact that TRP channel activity can be recorded in cially those for whom channel activities have been measured the plasma membrane using functional assays, and that TRP in their residing compartments. proteins can be detected in the plasma membrane using surface labeling techniques, the majority of heterologously- Overview of intracellular organelles expressed and many of the endogenous TRP proteins are In most mammalian cells there are at least eight different located intracellularly (for example see Refs Turner et al. types of intracellular organelles, which can be arbitrarily 2003; Bezzerides et al. 2004; Krapivinsky et al. 2006; Dong divided into two groups (Michelangeli et al. 2005). The first et al. 2008; Lange et al. 2009; Oancea et al. 2009). The endocytic, secretory and autophagic group (group I) includes molecular identities of these intracellular TRP-residing the endoplasmic reticulum (ER), the Golgi apparatus, compartments are poorly defined. It remains unclear whether secretory vesicles/granules, endosomes, autophagosomes, TRPs appear in these compartments as intermediates of and lysosomes (see Fig. 2). These group I organelles biosynthetic pathways being shuttled to their ultimate exchange materials with each other, either directly by destinations, or if they are active participants in signal complete or partial (‘kiss and run’) membrane fusion, or transduction and/or membrane trafficking. If the latter is true, with the aid of intermediate transport vesicles that bud off the larger question arises as to how TRPs function in vesicles (membrane fission) from the donor membrane and migrate to and are activated and/or modulated by cellular cues. TRPs the target membrane (Piper and Luzio 2004; Roth 2004; localized to the plasma membrane (PM TRPs) are modulated Luzio et al. 2007b; Stenmark 2009). In specialized cell by G protein signaling, lipid signaling, and protein phos- types, there are also cell-type-specific vesicular compart- phorylation and de-phosphorylation events (Clapham 2003; ments derived from endocytic and secretory pathways. For Ó 2010 The Authors Journal Compilation Ó 2010 International Society for Neurochemistry, J. Neurochem. (2010) 113, 313–328 TRP calcium channels in intracellular organelles | 315 example melanosomes, which release melanin in response to 2007). Evidence now exists, however, suggesting that light, are specialized lysosome-related organelles (LROs) in intracellular traffic is also highly regulated. The final trigger melanocytes (Blott and Griffiths 2002). In neurons, synaptic of intracellular membrane fusion is also likely to be a rise of 2+ vesicles that release neurotransmitters upon electrochemical [Ca ]cyt, whose amplitude and duration might be in a scale stimulation are derived from endosomes