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.

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

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

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