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