Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TRP (Transient Receptor Potential Cation Channel)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_72

Synonyms

Historical Background

Calcium is integrated in many physiological processes like muscle contraction, hormone secretion, and intracellular signaling processes (calcium signaling). Prerequisite for this role is the 10,000-fold gradient across the plasma membrane with 2.5 mM extracellular and resting intracellular calcium ion concentration of approximately 100 nM. Calcium ATPases ( Plasma membrane calcium-transporting ATPase) and transporters manage the extrusion of calcium whereas calcium-permeable ion channels enable rapid increases in intracellular calcium up to micromolar concentrations. The biological functions of calcium are mediated by direct calcium binding of the modulated proteins or by protein–protein interaction with calcium sensor proteins (calmodulin, CaBP, calcineurin, S100, NCS, etc.). In excitable cells like neurons, heart or skeletal, or smooth muscle cells, the calcium current is mediated by voltage–gated calcium channels. The molecular identity of the ion channels mediating hormone-induced calcium entry in non-excitable cells like endothelial, epithelial, immune cells remained mysterious for a long time. While it was clear that in mammals, receptor-stimulated calcium entry depends on the phospholipase C activity, parallelly in Drosophila melanogaster, a protein named Transient Receptor Potential (TRP) was identified and described as a phospholipase C–modulated, calcium-permeable ion channel involved in phototransduction (Montell and Rubin 1989). Upcoming genome and expression profiling projects with expressed sequence tags allowed the cloning of the first mammalian TRP-homologous proteins, the ion channels of the classic TRP family (TRPC). Other approaches identified additional TRP-homologous proteins establishing the melastatin-like and vanilloid-like TRP subfamilies, TRPM and TRPV, respectively (Harteneck et al. 2000; Montell et al. 2002; Wu et al. 2010). With the identification of TRPV1 (vanilloid receptor 1, VR1) as molecular target of capsaicin, another fascinating feature of TRP channels being target of many secondary plant compounds became obvious as well as the involvement of TRP channels in sensory functions (Caterina et al. 1997). Nowadays, the TRP superfamily comprises also the mucolipins (TRPML) and the polycystines (TRPP), calcium-permeable channel proteins with similar transmembrane topology and other similarities (Montell et al. 2002; Venkatachalam and Montell 2007; Wu et al. 2010). Despite their common structure and sequence identities, the members of the TRP superfamily are involved in many different cellular functions and are integrated in a variety of physiological processes. The basis for the versatility being integrated in so many signaling cascades is founded in the fact that TRP channels as nonselective ion channels are permeable for sodium, calcium, and other divalent cations. The ratio for the main charge carriers, sodium and calcium, varies within the superfamily from highly calcium-selective ion channels (TRPV5 and TRPV6) to calcium-activated, calcium-impermeable, sodium channels (TRPM4 and TRPM5) and represents an important biophysical feature for the characterization of TRP channels in a physiological context.

For the identification, cloning, and biochemical and physiological characterization, common experimental approaches are used, whereas patch clamp as well as calcium imaging techniques provide direct evidence of the channel activity. The patch clamp techniques use small pipettes and directly measure currents carried by the channels studied, whereas calcium imaging approaches depend on intracellular calcium-binding indicator dyes showing differences in fluorescence in the presence and absence of calcium, thereby allowing the measuring of intracellular calcium concentration as a readout of channel activity. The following entry will give an introduction in the broad field of TRP channel research orientated on the TRP channel classification.

TRPA1 Channel as Signaling Molecule

TRPA1 was initially cloned starting from an up-regulated EST in many tumor cells and described as ANKTM1 based on the most significant structural property of the protein sequence, the abundance of many N-terminal ankyrine-like repeats (Basbaum et al. 2009; Patapoutian et al. 2009). This feature, ANKTM shares with the fly and worm TRP channels of the NOMPC family. The NOMPC channels of Drosophila melanogaster and Caenorhabditis elegans are involved in mechanotransduction. Based on the similarity, mammalian ANKTM1 was temporarily discussed as putative mechanosensitive ion channels probably involved in hearing (Christensen and Corey 2007). The absence of deafness in ANKTM knockout animals however showed that ANKTM1 is not involved in hearing. TRPA1 plays an important role as cold and chemo sensor in mammalian nociceptive neurons. As protein sensing cold temperatures, TRPA1 is also activated by several cooling compounds like menthol or icilin and on the other hand by many pungent structures like allylisothiocyanate (mustard oil) or allicin or methyl paraben or cinnamaldehyde. The great variety of chemical structures activating TRPA1 and thereby mediating pain and triggering inflammatory processes makes TRPA1 an important target in the pain field.

TRPC Channels as Signaling Molecules

The classic TRP channel family comprises seven different genes with proteins showing the highest sequence similarity to the prototypic Drosophila TRP (Harteneck et al. 2000; Montell and Rubin 1989; Venkatachalam and Montell 2007; Wu et al. 2010). Like the prototypic fly channel, the mammalian channel proteins are involved in receptor-regulated calcium entry (Birnbaumer 2009). Stimulation of receptors by hormones, neurotransmitter (GPCR, photoreceptor), and light in Drosophila results in the phospholipase C–mediated breakdown of phosphatidylinositides, leading to the formation of inositol 1,4,5-triphosphate and diacylglycerol (Fig. 1). Inositol 1,4,5-triphosphate induces calcium release from intracellular stores via the activation of inositol 1,4,5-triphosphate receptors ( IP3 Receptor–Associated cGMP Kinase Substrate a), whereas diacylglycerol directly activates mammalian classic transient receptor potential (TRPC) channels (TRPC2, TRPC3, TRPC6, and TRPC7) in a protein kinase C–independent manner. The prerequisite of phospholipase C stimulation has been shown for TRPC1, TRPC4, and TRPC5 currents; however, the molecular mechanism is still unclear.
TRP (Transient Receptor Potential Cation Channel), Fig. 1

Activation pathway of mammalian receptor-activated TRPC channels. G-protein-coupled receptor (GPCR)–mediated activation of phospholipase C isoforms (PLC ßγ) result in the breakdown of phosphatidylinositides (PIP2), leading to the formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is the ligand of IP3 receptors, which are located in the endoplasmic reticulum. Upon activation, IP3 receptors mediate Ca2+ release from intracellular stores, whereas DAG directly activates mammalian TRPC2, TRPC3, TRPC6, and TRPC7 channels. In contrast to the current molecular understanding of the signaling cascade resulting in the stimulation of TRPC2, TRPC3, TRPC6, and TRPC7, the molecular mechanism for the stimulation of TRPC1, TRPC4, and TRPC5 is unclear. The prerequisite of phospholipase C activation in the activation of TRPC1, TRPC4, and TRPC5 is accepted

TRPC1 is transcribed in nearly all cells, whereas the other TRPC channels show a distinct and characteristic expression profile being adapted to cellular requirements; nevertheless, in many cell types, two and more TRPC channels can be found. On the other hand, the broad expression profile of TRPC channels makes it difficult to assign distinct physiological function to one gene. TRPC2 being expressed in the rodent vomeronasal organ is clearly an exception. In man, TRPC2 is a pseudogene; the transcribed mRNA is functionless due to various stop codons. However, in rodents, the transcription of the TRPC2 gene results in a functionally active protein involved in sensory response to pheromones. Genetic inactivation of TRPC2 in mice leads to loss of sex discrimination of male mice. Data from TRPC4 knockout mice approaches show that TRPC4 is involved in microvascular permeability. TRPC3 and TRPC5 are discussed to be involved in neuronal differentiation and growth cone guidance. TRPC6 expressed in vascular smooth muscle cells was discussed to be involved in blood pressure regulation. However, the characterization of TRPC6 knockout mice surprisingly showed a slightly increased blood pressure resulting from increased basal activity of TRPC3, up-regulated in TRPC6 knockout mice. The diversity of cellular function of the genes of the TRPC family became visible by reports showing that gain-of-function mutations of TRPC6 resulted in progressive kidney failure and focal segmental glomerulosclerosis (FSGS). The physiological role of TRPC6 in the kidney proposed from the analysis of the genetic disease is that TRPC6 expressed in podocytes is involved in hormone-dependent size regulation of the glomerular slit-diaphragm. Gain-of-function mutation of TRPC6 results in increased calcium load of the podocytes, induction of calcium-dependent apoptosis, progressive loss of podocytes, and glomerulosclerosis responsible for proteinuria found in these patients. The complexity of the different physiological function mediated by TRPC6 became obvious, when TRPC6 was identified as the molecular target of hyperforin, the active principle of St. John Wort extracts, a remedy for the treatment of moderate to mild depression (Fig. 2). The antidepressive action of hyperforin results from the direct activation of TRPC6, leading to enhanced intracellular calcium as well as sodium concentrations. By increasing intracellular sodium, the neurotransmitter uptake is indirectly inhibited by the impairment of the electrochemical gradient of sodium as basis for the reuptake of serotonin, dopamine, and noradrenaline. Like synthetic antidepressive drugs directly blocking the neurotransmitter transporter, hyperforin mediates neurotrophic effects in a TRPC6-dependent manner probably by calcium-induced differentiation processes. Calcium-dependent differentiation processes are regulated in a dual manner. Hyperforin or diacylglycerol concentration regulates TRPC6 activity and thereby the intracellular calcium concentrations. On the other hand, puromycin treatment of rats leads to increased TRPC6 expression in podocytes and proteinuria, whereas treatment of keratinocytes with betulin or other triterpens also increases TRPC6 expression and enhances keratinocytes differentiation. The duality of wanted as well as unwanted effects induced by the modulation of TRPC6 expression and activity demonstrates that the intracellular calcium concentrations are regulated within a tight interval with serious effects in case of imbalances. These observations transmitted to drug research and therapy show that both blocking as well as stimulating strategies will make sense in particular pathophysiological situations.
TRP (Transient Receptor Potential Cation Channel), Fig. 2

Proposed model of hyperforin-induced, TRPC6-mediated effects in neurons. Synthetic antidepressants block plasma membrane neurotransmitter transporter proteins, thereby increasing concentration and exposure time of neurotransmitters. In contrast to this mode of action, the antidepressive effects of hyperforin are mediated using another pathway. By activation of TRPC6 channels permeating sodium and calcium, the electrochemical gradient of sodium across the plasma membrane prerequisite for the function of the plasma membrane neurotransmitter transporter is reduced, resulting in an indirect inhibition of neurotransmitter uptake. On the other hand, TRPC6-mediated calcium entry may trigger calcium-dependent differentiation processes responsible for changes in neuronal plasticity by still unclear intracellular pathways

TRPM Channels as Signaling Molecules

Melastatin, the founding member of the melastatin-like TRP family, was identified within a screen for proteins differentially regulated in melanocytes and melanoma cells (Harteneck 2005; Venkatachalam and Montell 2007; Wu et al. 2010). Analysis of clinical data showed that the presence of melastatin expression in melanoma patients inversely correlates with the severity and survival. Although melastatin is the first member of the TRPM family, its activation mechanism and physiological role is still unclear. In line with the first description as protein involved in melanocyte physiology, several reports confirmed this view. A completely unexpected function, the integration in retinal signal processing, has recently been discovered by the identification of TRPM1 expression in retinal ON bipolar cells. The critical role of TRPM1 in mammalian phototransduction is also highlighted by several reports describing TRPM1 mutations in patients suffering from congenital stationary night blindness.

From sequence similarity, TRPM3 is phylogenetically the closest neighbor to melastatin. Several stimuli for the activation of TRPM3 have been reported. TRPM3 is activated by hypotonic extracellular solution and represents together with TRPV4, the volume-regulated TRP channels in the kidney. With the help of pharmacological tools, calcium entry induced by the application of hypotonic extracellular solutions can be assigned to TRPV4 and TRPM3 (Harteneck and Reiter 2007; Liedtke 2007; Vriens et al. 2009; Woudenberg-Vrenken et al. 2009). While TRPV4 is activated by 4a-Isomers of phorbolesters and is blocked by ruthenium red, TRPM3 is activated by sphingosine and by pregnenolone-sulfate and blocked by gadolinium ions. TRPM3 is expressed in oligodendrocytes in the brain, in renal epithelial and pancreatic beta cells. The phylogenetically next neighbors to TRPM1 and TRPM3 are TRPM6 and TRPM7. Latter are involved in the body magnesium homeostasis. While TRPM7 is ubiquitously expressed, TRPM6 is expressed in epithelial cells of the gut and the kidney and responsible for magnesium absorption and reabsorption. Loss-of-function mutations in TRPM6 are linked to autosomal-recessive hypomagnesemia with secondary hypocalcemia. TRPM6 and TRPM7 as well as TRPM2 (see below) share a common structural feature. All three genes code for chimeric proteins combining a hexahelical transmembrane channel forming domain with a C-terminal enzymatic active domain. In the case of TRPM6 and TRPM7, the pore-forming domains are fused to atypical alpha kinase-like structures. The functional role for the enzymatic domain is still under dispute. TRPM6 and TRPM7 are permeable for magnesium and for other essential divalent cations like Ca2+, Zn2+, Mn2+, Co2+ as well as toxic cations like Ba2+, Sr2+, Ni2+, Cd2+ (Hoenderop and Bindels 2008; Woudenberg-Vrenken et al. 2009). While divalent ions are the preferentially carried ion of TRPM6- and TRPM7-mediated currents, TRPM4 and TRPM5 form ion pores impermeable for divalent ions and allow selectively sodium to pass. As sodium channels, TRPM4 and TRPM5 are paradoxically activated by increased intracellular calcium concentrations and represent calcium-activated calcium channels. TRPM4 being ubiquitously expressed is involved in the mast cell activation and the release of inflammatory mediators. Furthermore, TRPM4 contributes to the neurogenic regulation of blood pressure by modulating central catecholamine release. In contrast to TRPM4, the expression of TRPM5 is restricted to a few cell types. TRPM5 is expressed in taste buds of the tongue and involved in the sensation of bitter and sweet taste. The remaining two TRPM channels proteins, TRPM2 and TRPM8, can also be discussed in the light of sensory functions. As already mentioned, TRPM2 represents a chimeric protein having an ADP-ribose hydrolase domain C-terminal to the pore-forming transmembrane domains. Simultaneously to the ADP-ribose hydrolysing activity of the C-terminal enzymatic domain, TRPM2 is activated by ADP-ribose and it has been shown that the C-terminal part is essential for the function as pore-forming channel protein. Increased intracellular ADP-ribose concentrations are linked to genotoxic and/or oxidative stress of cells, leading to the activation of the poly(ADP-ribose) polymerase (PARP) modulating protein stability by the mono- and poly-ADP-ribosylation of proteins. This process of protein stability regulation is additionally controlled by an enzyme called poly(ADP-ribose) glucohydrolase (PARG). PARG reduces the posttranslational poly-ADP-ribose modifications to mono-ADP-ribosylation, thereby increasing the intracellular ADP-ribose concentration leading to the activation of TRPM2. In whole cell calcium imaging experiments, the extracellular application of hydrogen peroxide results in the activation of TRPM2 validating its function as redox sensor. While TRPM2 is highly expressed in immune cells and at low levels in some neurons making the discussion of TRPM2 as redox sensor difficult, TRPM8, the cold sensor, is mainly expressed in sensory neurons. TRPM8 is activated at temperatures between 8 °C and 28 °C as well as secondary plant compound menthol and synthetic cooling compounds. Together with TRPA1, TRPM8 represents the cold sensors in human. Noxious cold is mediated by TRPA1 (Fig. 3).
TRP (Transient Receptor Potential Cation Channel), Fig. 3

TRP channels as thermo sensors. The diagram summarizes the secondary plant compounds and temperature ranges activating temperature-sensitive TRP channels. TRPA1 is activated by pungent and cooling compounds and is activated by temperatures below 17 °C, whereas TRPM8 is activated at temperatures below 27 °C and cooling compounds like menthol. TRPV4 is activated at intermediate temperatures and extracellular hypotonic solutions (see volume-regulated TRP channels TRPV4 and TRPM3). TRPV3 mainly expressed in keratinocytes is activated by temperature from 31 °C to 39 °C and camphor. TRPV1, also named vanilloid receptor 1 or capsaicin receptor 1, is activated by capsaicin and temperature above 42 °C, whereas TRPV2 is activated by heat above 51 °C

TRPML Channels as Signaling Molecules

Mucolipidosis Type IV is an autosomal-recessive neurodegenerative lysosomal storage disorder caused by mutations in TRPML 1 (Montell et al. 2002; Puertollano and Kiselyov 2009). TRPML1 like the other members of the mucolipin family (TRPML1-3) is described to be located as integral membrane proteins of intracellular vesicles especially the lysosomes and probably activated by protons. The lysosomes in mucolipidosis IV patients are enlarged arguing for defects of the intracellular turnover and storage of lipids such as phospholipids, sphingolipids, gangliosides, and mucopolysaccharides. Based on this observation, a contribution of mucolipin channels in the intracellular trafficking and handling of lysosomes is discussed and provides hypotheses for further research.

TRPP Channels as Signaling Molecules

The autosomal-dominant polycystic kidney disease (ADPKD) is characterized by cysts formation in the kidney, a malformation of the renal tubular structure (Montell et al. 2002; Zhou 2009). The cyst formation is linked to the disruption of the functional TRPP1/TRPP2 complex. TRPP1, a huge protein consisting of a complex N-terminal extracellular ligand binding and 11 transmembrane domains, and TRPP2, a calcium-permeable ion channel, form a receptor–effector complex implicated in various biological functions, such as cell proliferation, sperm fertilization, and mechanosensation.

TRPV Channels as Signaling Molecules

Vanilloid structures, derivates of vanillin comprising eugenol, zingerone, and capsaicin, are found in many splice plants and known for their individual characteristic flavor. Beside the use as spice, vanilloid-containing plant extracts are used as remedy in the various traditions of folk medicine. The therapeutic and experimental uses of capsaicin in pain treatment inspired research resulting in the unraveling of the molecular target of capsaicin. The molecular target, an ion channel related to Drosophila TRP, was named capsaicin or vanilloid receptor and became eponym of the subgroup or structurally related ion channels of the TRP channel superfamily (Caterina et al. 1997). The vanilloid-like TRP channels comprise six members, four proteins (TRPV1 to TRPV4) like TRPV1 are nonselective ion channels involved in thermosensation (Basbaum et al. 2009; Liedtke 2007; Talavera et al. 2008; Vriens et al. 2009; Wu et al. 2010), while two ion channels (TRPV5 and TRPV6) represent highly calcium-selective ion channels (Hoenderop and Bindels 2008; Woudenberg-Vrenken et al. 2009). Initially described as calcium transporter, TRPV5 and TRPV6 are responsible for the uptake and reuptake of calcium in the gut and kidney, respectively. Expressed in the epithelial cell layers of the gut and kidney, the activity is transcriptionally controlled in a vitamine-D3-dependent manner.

Capsaicin, the ingredient in chili pepper, causing burning and pain activates TRPV1, the heat sensor, activated by increased temperatures under physiological conditions. The capsaicin receptor being expressed in dorsal root ganglia senses increasing temperatures with a threshold of around 42 °C. The activation of TRPV1 is realized as heat and burning, the same sensation caused by capsaicin. Illustrative for the modulation of the 42 °C threshold of TRPV1 is the burning pain after the application of ethanol or acids in wounds as TRPV1 activity is dramatically enhanced at normal body temperature in the presence of increased proton concentration or in the presence of around 3% ethanol. Since the first description of TRPV1 as the molecular target of capsaicins, many pain-inducing chemicals and toxins have been described as TRPV1 ligands. The warm and heat sensors (TRPV1 to TRPV4) and the cold sensors (TRPM8 and TRPA1) represent the thermosensors of the human body and cover the complete temperature range necessary for human life (Fig. 3). As warning sensors expressed in dorsal root ganglia, the thermo-TRPs are also involved in sensation and modulation of pain and therefore interesting as molecular targets for new pain-treating drugs.

Summary

Transient receptor potential (TRP) channels are a large family of nonselective, calcium-permeable channel proteins activated and regulated by a diversity of mechanisms. TRP channels respond to intracellular stimuli such as calcium, metabolites of the arachidonic acid, or phosphatidylinositol signal transduction pathways. TRP channels sense environmental stimuli such as changes in temperature, osmolarity, and pH and represent the molecular target of pheromones, taste, and secondary plant compounds. The broad function in physiology proposed by the expression profiles of TRP channels becomes visible by the association of TRP channel mutations with hereditary diseases or the analysis of TRP channel knockout mice. The diversity of the chemical structures and the selectivity of the natural occurring compounds modulating TRP channels show the possibility for the pharmacological modulation of TRP channels and inspire to develop new synthetic structures for TRP channel interference at bench and bedside.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and Experimental Therapy, Institute of Experimental and Clinical Pharmacology and ToxicologyInterfaculty Center of Pharmacogenomics and Pharmaceutical Research (ICePhA), Eberhard-Karls-UniversityTübingenGermany