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 G_q-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 P_Ca:P_Na 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

References

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