Transient Receptor Potential Channels
The transient receptor potential family of ion channels consists of at least 28 mammalian members divided into six subfamilies: 7 TRPC (canonical), 6 TRPV (vanilloid), 8 TRPM (melastatin), 1 TRPA (ankyrin), 3 TRPP (polycystin) and 2 TRPML (mucolipin). Numerous invertebrate TRP channels have also been identified, including the prototypical “transient receptor potential” channels from Drosophila photoreceptors, TRP and TRP-like, and there is growing evidence for evolutionary conservation of their roles in cellular physiology and sensory biology.
Structurally, TRP channels have six transmembrane domains and intracellular amino and carboxyl termini. Four subunits apparently comprise a functional channel. Other features shared by some, but not all, TRP channels include a TRP-domain found in the proximal portion of the sixth transmembrane domain of all TRPC and some TRPM channels, and a string of 3-14 ankyrin repeat domains found in the amino terminus of TRPC, TRPV and TRPA channels. Sequence homology among all family members is concentrated in ankyrin repeat, transmembrane, and TRP domains, and can be as little as ~20% overall. Functionally, TRP channels are versatile molecules that can be gated by G protein-coupled receptor (GPCR) signaling, lipids, ions, osmolarity, voltage, or even hot and cold temperatures. Upon activation, these channels mediate the influx of monovalent and/or divalent cations into excitable and nonexcitable cells.
There appears to be only one mammalian member of the TRPA subfamily, referred to as TRPA1. This channel contains 14 ankyrin repeat domains in its amino terminus. It is expressed in several locations, including a subset of primary sensory neurons and in hair cells of the inner ear. This channel can be activated by pungent compounds such as mustard oil (allyl isothiocyanate) or cinnamaldehyde. It has also been reported to be activated by painful cold (<20 °C), although this claim has been disputed. There is also evidence that TRPA1 may contribute to mechanotransduction mechanisms in the auditory and vestibular systems.
The TRPC subfamily can be further subdivided into several groups. TRPC1 is a widely distributed subtype that can form heteromultimers with other TRPC subfamily members. The TRPC2 gene is expressed in rodents, but is a psudogene in humans. This channel is specifically expressed in the sensory cilia of vomeronasal organ pheromone sensing cells, and is essential for certain GPCR-mediated pheromone-driven behaviors in mice. TRPC4 and TRPC5 form homomultimeric channels, as well as heteromultimers that include TRPC1. They are activated by Gq-coupled GPCR signaling pathways via an as yet unidentified mechanism. TRPC3, TRPC6, and TRPC7 can be activated directly by diacylglycerol. All TRPC channels pass nonselective cationic currents. It is believed that some TRPC channels participate in so-called “store-operated” Ca2+ entry into cells following depletion of IP3 receptor-dependent intracellular Ca2+ stores. However, the mechanisms underlying this process have been debated. One proposal suggests conformational coupling between intracellular IP3 receptors and cell surface TRPC channels. Other investigators have argued for the existence of a diffusible messenger that regulates store-operated channel function.
The TRPM subfamily is characterized by exceptionally long amino and/or carboxyl terminal domains. TRPM1 is downregulated during metastatic progression of melanoma cells, although its functional properties are unknown. TRPM2 is a nonselective cation channel possessing a C-terminal NUDIX domain that allows this channel to be activated by ADP-ribose, NAD and reactive oxygen species. TRPM3 forms a nonselective cation channel with constitutive activity that can be augmented by hypoosmolarity and may play a role in renal Ca2+ homeostasis. TRPM4 and TRPM5 are voltage-dependent channels selective for monovalent cations that both exhibit extracellular Ca2+-dependent activation. Furthermore, TRPM4 can be regulated by intracellular adenine nucleotides or by decavanadate ions. TRPM6 and TRPM7 appear to form heteromultimeric divalent cation-selective channels that are critical for Mg2+ homeostasis in humans. They also contain an intrinsic kinase domain within their carboxyl terminus that regulates responsiveness to intracellular Mg2+. TRPM8, originally identified as being prostate-specific, was subsequently found to be expressed in a subset of sensory neurons and to respond to modestly cold temperatures (<28 °C) and the cold-mimetic chemicals, menthol and icilin. Icilin activation, however, requires intracellular Ca2+ as a co-agonist. This nonselective cation channel also exhibits voltage-dependent opening.
The TRPV subfamily is so-named because its founding member, TRPV1, is the receptor for capsaicin, the major pungent component of “hot” chili peppers and other compounds (e.g., resiniferatoxin) that possess a similar vanilloid chemical moiety. This channel is highly expressed in nociceptive sensory neurons that detect painful stimuli. TRPV1 can also be activated by protons, endocannabinoid compounds, or elevated temperature (>42 °C). Accordingly, responses to all of these stimuli are diminished or absent in TRPV1 knockout mice. TRPV2, TRPV3, and TRPV4 can also be activated by heat, with temperature thresholds of ~ 52 °C, ~34 °C and ~27 °C, respectively. Alternatively, TRPV4 can be activated by hypoosmolarity or certain epoxyeicosatrienoic acids and TRPV2 can be activated by hypoosmolarity or growth factor receptor stimulation. TRPV4 is necessary for normal maintenance of serum osmolarity in the mouse. All four of these proteins form homomultimeric nonselective cation channels with a PCa:PNa of 5-10:1. TRPV5 and TRPV6 form homomultimeric and heteromultimeric Ca2+-selective channels that exhibit constitutive activity and participate in Ca2+ uptake in the intestine and kidney.
The Tables below contain accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.
Ankyrin and Canonical Subfamilies | ||||
---|---|---|---|---|
Name | TRPA1 | TRPC1 | TRPC2 | TRPC3 |
Alternative Names | ANKTM1 | TRP1 | Not Known | mTRPC3 |
Structural Information | 1119 aa (human) 1125 aa (mouse) | 793 aa (human) 809 aa (mouse) | Human pseudogene 1172 aa (mouse) | 848 aa(human) 836 aa (mouse) |
Activators | Mustard oil (W203408) Cinnamaldehyde (W228613) Ca2+ (intracellular) Cold (<20°C) THC (T2386) | GPCR-Gq -PLC | GPCR-Gq -PLC | DAG Direct interaction with IP3R |
Inhibitors | Ruthenium red (R2751) Gd3+ (homomer) | 2-APB (heteromer w/C1) (D9754) La3+ (heteromer w/C1) Gd3+ (homomer) High external Ca2+ 2-APB (D9754) | Not Known | 2-APB (D9754) PMA (P8139) |
Modulators | Icilin (I9532) | Calmodulin (P0270, P1431) | Not Known | Not Known |
Signal Transduction Mechanism | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel |
Radioligand of Choice | Not Known | Not Known | Not Known | Not Known |
Tissue Expression | Sensory neurons, inner ear hair cells, vestibular organ | Heart, brain, testis, ovary | Vomeronasal organ, testis | Brain |
Physiological Effects (demonstrated or speculated) | Cold-evoked pain, chemically evoked pain | Cellular Ca2+ homeostasis | Pheromone detection | Cellular Ca2+ homeostasis |
Disease States (demonstrated or speculated) | Chronic pain, cancer, deafness | Not Known | Unlikely in humans | Not Known |
Name | TRPC4 | TRPC5 | TRPC6 | TRPC7 |
---|---|---|---|---|
Alternative Names | TRP4, CCE1, bCCE | TRP5, CCE2 | Not Known | TRP7 |
Structural Information | 982 aa (human) | 973 aa (human) 975 aa (mouse) | 931aa (human) 930aa (mouse) | 862aa (human) 862 aa (mouse) |
Activators | Weakly voltage dependent GPCR-Gq -PLC | Weakly voltage dependent GPCR-Gq -PLC | DAG | DAG |
Inhibitors | 2-APB (D9754) | 2-APB (D9754) | Not Known | La3+ SKF96365 (S7809) |
Modulators | La3+ (augments currents) | La3+ (augments currents) | Not Known | Extracellular ATP intracellular Ca2+ PKC |
Signal Transduction Mechanism | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel |
Radioligand of Choice | Not Known | Not Known | Not Known | Not Known |
Tissue Expression | Brain, endothelium, adrenal gland, retina, testis | Brain | Lung, brain | Eye, heart, lung |
Physiological Effects (demonstrated or speculated) | Cellular Ca2+ homeostasis, vascular tone, permeability, neurotransmitter release | Cellular Ca2+ homeostasis, neurite outgrowth | Cellular Ca2+ homeostasis, cerebrovascular tone | Cellular Ca2+ homeostasis |
Disease States (demonstrated or speculated) | Hypertension | Not Known | Not Known | Not Known |
Abbreviations
2APB: 2-Aminoethoxydiphenyl borate
SB366791: N-(3-Methoxyphenyl)-4-chlorocinnamide
BCTC: N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide
EGF: Epidermal growth factor
GPCR: G protein-coupled receptor
4α-PDD: 4 α-Phorbol didecanoate
DAG: Diacylglycerol
IP3R: Inositol triphosphate receptor
NAD: Nicotinamide adenine dinucleotide
NUDIX: Nucleoside diphosphate pyrophosphatase
PMA: Phorbol myristoyl acetate
PIP2: Phosphatidyl inositol bisphosphate
PLC: Phospholipase C
THC: Δ 9-Tetrahydrocannabinol
Melastatin Subfamily | ||||
---|---|---|---|---|
Name | TRPM1 | TRPM2 | TRPM3 | TRPM4 |
Alternative Names | Melastatin | TRPC7, LTRPC7 | KIAA1616, LTRPC3 | FLJ20041, LTRPC4 |
Structural Information | 1533 aa (human) 1749 aa (mouse) | 1503 aa (human) 1507 aa (mouse) C term. NUDIX domain | 1707 aa (human) 1337 aa (mouse) | 1214aa (human) 945 aa (mouse) |
Activators | Constitutively active | β-NAD ADP-ribose (A0752) H2O2 (H3410) | Constitutive | Extracellular Ca2+ |
Inhibitors | La3+ | Na+ | Not Known | Mg2+ La3+ Adenine nucleotides |
Modulators | Not Known | Intracellular Ca2+ TNFα (T7539, T6674, T5944) Arachidonic acid (A3555, A3611, A8798) | Hypotonicity (increase) | Decavanadate |
Signal Transduction Mechanism | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel | Monovalent-selective cation channel |
Radioligand of Choice | Not Known | Not Known | Not Known | Not Known |
Tissue Expression | Eye, melanocytes | Brain, pancreas, neutrophils | Kidney, brain | Prostate, colon, heart, kidney, neurons |
Physiological Effects (demonstrated or speculated) | Tumor supressor, calcium homeostasis | Oxidative stress response, apoptosis | Renal calcium homeostasis | Cellular Ca2+ homeostasis |
Disease States (demonstrated or speculated) | Melanoma | Not Known | Not Known | Not Known |
Name | TRPM5 | TRPM6 | TRPM7 | TRPM8 |
---|---|---|---|---|
Alternative Names | Mtrl, LTRPC5 | ChaK2 | TRP-PLIK, LTRPC7, ChaK(1) | Trp-p8, CMR1 |
Structural Information | 1165 aa (human) 1148 aa (mouse) | 2022 aa (human) 2028 aa (mouse) C term. a-kinase domain | 1865 aa (human) 1863 aa (mouse) C term. a-kinase domain | 1104 aa (human) 1104 aa (mouse) |
Activators | Extracellular Ca2+ | Low intracellular Mg2+ and Mg2+ ATP | Low intracellular Mg2+ and Mg2+ ATP Constitutive | Menthol (M2772) Icilin (I9532) (coagonist w/Ca2+) Cold (<27 °C) Eucalyptol (C80601) |
Inhibitors | Not Known | Not Known | Mg2+ La3+ | 2-APB (D9754) Low pH |
Modulators | PIP2 (P9763) | Not Known | PIP2? (P9763) | Not Known |
Signal Transduction Mechanism | Monovalent-selective cation channel | Ca2+- and Mg2+- selective channel | Ca2+- and Mg2+- selective channel | Non-selective cation channel |
Radioligand of Choice | Not Known | Not Known | Not Known | Not Known |
Tissue Expression | Small intestine, liver, lung | Colon, kidney | Kidney, heart | Prostate, sensory neurons |
Physiological Effects (demonstrated or speculated) | Taste transduction | Cell Mg2+ homeostasis, Mg2+ absorbtion | Cell Mg2+ homeostasis, Mg2+ absorbtion | Cold sensation, cancer |
Disease States (demonstrated or speculated) | Not Known | Not Known | Hypomagnesemia | Cold pain, prostate cancer |
Abbreviations
2APB: 2-Aminoethoxydiphenyl borate
SB366791: N-(3-Methoxyphenyl)-4-chlorocinnamide
BCTC: N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide
EGF: Epidermal growth factor
GPCR: G protein-coupled receptor
4α-PDD: 4 α-Phorbol didecanoate
DAG: Diacylglycerol
IP3R: Inositol triphosphate receptor
NAD: Nicotinamide adenine dinucleotide
NUDIX: Nucleoside diphosphate pyrophosphatase
PMA: Phorbol myristoyl acetate
PIP2: Phosphatidyl inositol bisphosphate
PLC: Phospholipase C
THC: Δ 9-Tetrahydrocannabinol
Vanilloid Subfamily | |||
---|---|---|---|
Name | TRPV1 | TRPV2 | TRPV3 |
Alternative Names | Vanilloid receptor (VR1), Capsaicin receptor | VRL-1, GRC, OTRPC1 | VRL-3, OTRPC2 |
Structural Information | 839 aa (human) 839 aa (mouse) | 764 aa (human) 756 aa (mouse) | 790 aa (human) 791 aa (mouse) |
Subtype-Selective Agonists | Capsaicin (M2028) Resiniferatoxin (R8756) Olvanil (O0257) Nuvanil N-arachidonyl dopamine (A8848) | Not Known | Not Known |
Activators with other Known Targets | Anandamide (A0580) Protons 2-APB (D9754) Heat (>42 °C) | Hypoosmolarity heat (>52 °C) 2-APB (D9754) | Heat (>34 °C) 2-APB (D9754) |
Receptor-Selective Antagonists | SB366791 (S0441) 5'-iodoresiniferatoxin (I9281) | Not Known | Not Known |
Antagonists with other Known Activities | Capsazepine (C191) BCTC (SML0355) Ruthenium red (R2751) | Ruthenium red (R2751) | Ruthenium red (R2751) |
Modulators | Protons Sulfhydryl reagents Nerve growth factor (indirect) GPCR-Gq activation (indirect) | EGF (indirect) | Not Known |
Signal Transduction Mechanism | Non-selective cation channel | Non-selective cation channel | Non-selective cation channel |
Radioligand of Choice | [3H] Resiniferatoxin | Not Known | Not Known |
Tissue Expression | Sensory neurons, brain, urinary bladder epithelium, skin keratinocytes, mast cells, hepatocytes | Sensory neurons, brain, lung, skeletal, cardiac muscle, intestines, mast cells | Sensory neurons, brain, skin keratinocytes, testis |
Physiological Effects (demonstrated or speculated) | Pain sensation, bladder contraction, vasomotor regulation, immunoregulation | Pain sensation, Mast cell function | Pain, warmth sensation |
Disease States (demonstrated or speculated) | Chronic pain, bladder hyperactivity, inflammatory bowel disease, Prurigo nodularis | Chronic pain | Chronic pain |
Name | TRPV4 | TRPV5 | TRPV6 |
---|---|---|---|
Alternative Names | VRL-2, Trp12, VR-OAC, OTRPC4 | ECaC1, CaT2, OTRPC3 | ECaC2, CaT1, CaT-like |
Structural Information | 871 aa (human) 871 aa (mouse) | 729 aa (human) 723 aa (mouse) | 725 aa (human) 727 aa (mouse) |
Subtype-Selective Agonists | 4α-PDD | Not Known | Not Known |
Activators with other Known Targets | Hypoosmolarity Heat (>27 °C) 5', 6'-eicosatrienoic acid | Not Known | Not Known |
Receptor-Selective Antagonists | Not Known | Not Known | Not Known |
Antagonists with other Known Activities | Ruthenium red (R2751) | Ruthenium red (R2751) 2-APB (D9754) | Ruthenium red (R2751) |
Modulators | Not Known | Vitamin D (expression level) | Vitamin D (expression level) 2-APB (D9754) |
Signal Transduction Mechanism | Non-selective cation channel | Ca2+-preferring cation channel | Ca2+-preferring cation channel |
Radioligand of Choice | Not Known | Not Known | Not Known |
Tissue Expression | Kidney nephron, brain, skin keratinocytes, sensory neurons, respiratory epithelium, smooth muscle | Kidney, small intestine, placenta, pancreas | Small intestine, pancreas, placenta |
Physiological Effects (demonstrated or speculated) | Pain, warmth sensation, osmoregulation, mechanosensation | Calcium absorption | Calcium absorption |
Disease States (demonstrated or speculated) | Chronic pain, diabetes insipidus, asthma | Hypocalcemia | Hypocalcemia |
Abbreviations
2APB: 2-Aminoethoxydiphenyl borate
SB366791: N-(3-Methoxyphenyl)-4-chlorocinnamide
BCTC: N-(4-Tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide
EGF: Epidermal growth factor
GPCR: G protein-coupled receptor
4α-PDD: 4 α-Phorbol didecanoate
DAG: Diacylglycerol
IP3R: Inositol triphosphate receptor
NAD: Nicotinamide adenine dinucleotide
NUDIX: Nucleoside diphosphate pyrophosphatase
PMA: Phorbol myristoyl acetate
PIP2: Phosphatidyl inositol bisphosphate
PLC: Phospholipase C
THC: Δ 9-Tetrahydrocannabinol
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References
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