TRPV1b, a Functional Human Vanilloid Receptor Splice Variant

Lǚ, Gang; Henderson, Dorian; Liu, Lieju; Reinhart, Peter H.; Simon, Sidney A.

doi:10.1124/mol.104.009852

Cited by 69 publications

(69 citation statements)

References 42 publications

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“…Thus, the MPD of the N terminus emerged as the only component capable of perturbing the enthalpy of the channel. It is interesting that the region maps to the missing segment in the nonfunctional TRPV1b splice variant (21,27). The effectiveness of the region throughout different channels suggests that its function is conserved.…”

Section: Discussionmentioning

confidence: 99%

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

Yao

Liu

Feng

2011

Proc. Natl. Acad. Sci. U.S.A.

203

204

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The molecular basis of the thermal sensitivity of temperature-sensitive channels appears to arise from a specific protein domain rather than integration of global thermal effects. Using systematic chimeric analysis, we show that the N-terminal region that connects ankyrin repeats to the first transmembrane segment is crucial for temperature sensing in heat-activated vanilloid receptor channels. Changing this region both transformed temperature-insensitive isoforms into temperature-sensitive channels and significantly perturbed temperature sensing in temperature-sensitive wild-type channels. Swapping other domains such as the transmembrane core, the C terminus, and the rest of the N terminus had little effect on the steepness of temperature dependence. Our results support that thermal transient receptor potential channels contain modular thermal sensors that confer the unprecedentedly strong temperature dependence to these channels. chimera | temperature gating | temperature jump | thermosensation | pain T he ability to sense temperature is vital to living organisms. In mammals, the neural input on ambient temperature results from specialized groups of neurons that project to the skin. The transducers involve ion channels known as transient receptor potential (TRP) channels (1, 2), which constitute an array of biological thermometers responsive over a broad temperature gradient from noxious cold to noxious hot (3).The molecular mechanism by which temperature changes induce channel opening is not yet known, but the phenomenological tools to analyze the system are known from classical thermodynamic theory. The probability of channel opening follows a Boltzmann relationship to temperature. The enthalpy change (ΔH) between closed and open determines the slope sensitivity of the curve, whereas the entropy change (ΔS) affects its midpoint (T 1∕2 ). The term "threshold" is also commonly used in studies of temperature-sensitive channels to represent the change in temperature required for the response to be larger than the noise level of the recording. Changes in threshold could occur by changes in ∆H or T 1∕2 or the recording noise level.Thermodynamic analyses reveal that thermal TRP channels undergo large enthalpy changes, which accounts for their high temperature sensitivity (4-8). The opening of TRPV1, for example, involves an activation enthalpy of approximately 100 kcal/mol (7), five times the enthalpy change for ligand-or voltage-dependent gating [Q 10 ∼ 2-3 (ref. 9), equivalent to an enthalpy of approximately 20 kcal/mol]. If the free energy change were determined by enthalpy alone, the rate of gating would be very slow because the barrier would be too high. However, thermal TRP channels have evolved to have tightly coupled enthalpy and entropy changes so that the free energy change is relatively small (7). The threshold of activation summarizes the influence of all the temperature-insensitive processes that can regulate gating including the membrane potential (5, 6, 10) and any other allosteric sources such as li...

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Section: Discussionmentioning

confidence: 99%

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

Yao

Liu

Feng

2011

Proc. Natl. Acad. Sci. U.S.A.

203

204

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“…Another possibility is that TRPV1 triggers LTD via a nonconducting function (Kaczmarek, 2006) or via a capsaicin-resistant TRPV1. For example, the alternatively spliced variant TRPV1b has been described as a functional ion channel although it does not respond to capsaicin (Lu et al, 2005). Indeed, the authors reported TRPV1 expression [Cavanaugh et al (2011), their Fig.…”

Section: Review Of Cavanaugh Et Almentioning

confidence: 99%

The Expression Pattern of TRPV1 in Brain

Menigoz¹,

Boudes²

2011

J. Neurosci.

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“…Comparing the amplitude of the camphor response relative to the capsaicin response in each individual neuron, camphor current was between 5.8 and 71% (ϩ80 mV) of the 1 M capsaicin current. The lone camphor-responsive neuron that lacked capsaicinactivated current might have been the result of camphormediated desensitization of TRPV1 or may have expressed capsaicin-insensitive TRPV1 splice variants (Lu et al, 2005) or alternatively the presence of TRPV3 channels.…”

Section: Camphor Activation Of Trpv1-like Currents In Drg Sensory Neumentioning

confidence: 99%

Camphor Activates and Strongly Desensitizes the Transient Receptor Potential Vanilloid Subtype 1 Channel in a Vanilloid-Independent Mechanism

2005

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Camphor is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying molecular mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, respectively. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concentrations than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were observed in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.

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TRPV1b, a Functional Human Vanilloid Receptor Splice Variant

Cited by 69 publications

References 42 publications

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels

The Expression Pattern of TRPV1 in Brain

Camphor Activates and Strongly Desensitizes the Transient Receptor Potential Vanilloid Subtype 1 Channel in a Vanilloid-Independent Mechanism

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