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Table 1 Summary table of the mutants discussed in the article

From: Functionally important amino acid residues in the transient receptor potential vanilloid 1 (TRPV1) ion channel – an overview of the current mutational data

Residue Mutated to Role in the channel function / Impact of the mutation on the channel function Refs
C73 S Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [177]
I75 F Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
I76 T Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
V78 G Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
R114 A, E, Δ Its deletion or mutation abrogated vanilloid and proton activation and RTX binding, without effecting heat activation. [16]
R115 D Its mutation abrogated vanilloid activation and RTX binding, without effecting heat activation. [16]
S116 A The residue is phosphorylated by PKA and is involved in desensitization. It is also functional target for PKCμ. Its mutation abolished phosphorylation by PKCμ and enhanced the channel response to CAPS by PKCμ. [85, 90, 176, 210]
T144   Its phosphorylation by PKA causes sensitization of heat-evoked responses. [78, 83]
K155 A, E Its mutation caused impaired TRPV1-ARD interaction with ATP, and impaired tachyphylaxis, even in the absence of ATP. The mutant channel did not interact with CaM, and was slightly more sensitive to CAPS than the wild type. [14, 177]
Its mutation resulted in a constitutively active channel, and caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae.
C157   The residue is covalently modified by allicin causing allicin activation of the channel. [187]
K160 A, E Its mutation caused impaired TRPV1-ARD interaction with ATP, and impaired tachyphylaxis, even in the absence of ATP. The mutant channel did not interact with CaM, and was slightly more sensitive to CAPS than the wild type. [14, 177]
Its mutation resulted in a constitutively active channel, caused gain of function mutation and strong toxicity when expressed in Saccharomyces cerevisiae.
H166 R Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. Its mutation resulted in significant response to pH 6.4 (threshold concentration for proton-activation). [177]
D178 N Its mutation abolished the ATP-mediated upregulation of TRPV1. [205]
Y199 A, F When both sites were mutated, Y199/Q202 impaired the TRPV1-ARD interaction with ATP and ATP-mediated tachyphylaxis. The mutated channel was slightly more sensitive to CAPS than the wild type. Mutant channels formed a weaker complex with CaM than wild type but it still had a 1:1 stoichiometric ratio. [14, 211]
Phosphorylation of hTRPV1 Y200 (Y199 in rTRPV1) by Src kinase increases the surface expression of TRPV1 and accounts for rapid sensitizing actions of NGF. When mutated, Src-dependent, NGF-induced Tyr phosphorylation was completely abolished.
Q202 A When both sites were mutated, Y199/Q202 impaired the TRPV1-ARD interaction with ATP and ATP-mediated tachyphylaxis. The mutated channel was slightly more sensitive to CAPS than the wild type. Mutant channels formed a weaker complex with CaM than wild type but it still had a 1:1 stoichiometric ratio. [14]
N310 D Its mutation caused gain of function and weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
S343 G, R, Its mutation caused gain of function and strong/weak toxicity when expressed in Saccharomyces cerevisiae. [177]
A350 T Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [177]
I352 N, T Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. Its mutation also caused significant response to pH 6.4 (threshold concentration for proton-activation). [177]
T370   The residue is phosphorylated by PKA. It is involved in desensitization of the channel, and in the sensitization of heat-evoked TRPV1 responses when phosphorylated by PKA. [78, 83, 85, 176, 210]
F489 Y Mutation resulted in a rightward shift of the CAPS concentration of half-maximal activation. [167]
R491 E, G, Mutation caused reduction in CAPS sensitivity. [168]
S502 A Its phosphorylation by PKC potentiates CAPS, proton, and thermal responses, and that by PKA sensitizes the heat-evoked responses. [78, 83, 85, 91, 174, 209]
It is a CaMKII phosphorylation site.
When associated with T704I, S502A was found to lose the ability to be activated by CAPS and to lose the ability of vanilloid binding.
Its mutation reduced PMA enhancement of CAPS-evoked currents, but had no effect on direct activation by PMA.
Y511 A, C, F, Its mutation abolished CAPS responses, and RTX binding yet leave activation by heat and protons intact. [168171, 180]
S512 A, F, T, Y Its mutation abolished CAPS responses and RTX binding, yet left activation by heat and protons intact. It is involved in I-RTX binding. [168, 169, 173, 193]
Q519 N Its mutation ablated the vanilloid sensitivity. [168]
F522 L Its mutation ablated the vanilloid sensitivity. [168]
M523 L Its mutation ablated the vanilloid sensitivity. [168]
S532 C Its mutation ablated the vanilloid sensitivity. [168]
K535 E Its mutation ablated the vanilloid sensitivity, and affected proton responses. [168, 192]
E536 L, W Its mutation ablated the vanilloid sensitivity, and affected proton responses. [168, 192]
V538 A, G, I, L, T Its mutation ablated proton activation, but not the proton potentiation. [192]
A539 P Its mutation affected proton responses. [192]
M547 A, I, L, Q The residue is involved in RTX binding, CAPS sensitivity, I-RTX sensitivity and proton sensitivity. [168, 170, 171, 173, 180]
W549   It is involved in vanilloid binding. [171, 182]
T550 A, C, I, S, Y, Δ, It is an important molecular determinant in vanilloid sensitivity. Participates in Caps and RTX binding. [168, 170, 171, 180]
Its deletion reduced CAPS sensitivity of the channel.
R557 A, E, K, L It is involved in CAPS potentiation of heat-induced currents and in the transduction of the CAPS-binding signal to the opening of the pore. [179]
It is also important in deactivation gating process, 2-APB activation and for voltage-dependent gating.
It contributes to the voltage modulation of the CAPS-induced currents and the CAPS potentiation of the heat-induced currents.
Q560 H, R It is involved in the transduction of the CAPS-binding signal to the opening of the pore. [177, 179]
It is also important in deactivation gating process and for 2-APB activation.
Its mutation caused significant response to pH 6.4 (threshold concentration for proton-activation).
Its mutation caused gain of function of the channel and weaker toxicity when expressed in Saccharomyces cerevisiae.
Q561 H, R Its mutation caused gain of function of the channel and strong toxicity when expressed in Saccharomyces cerevisiae. [177]
M562 D Its mutation caused significant response to pH 6.4 (threshold concentration for proton-activation). [177]
G563 S The residue is involved in the voltage gating of the channel. [179]
E570 A, L, Q, R The residue contributes to the voltage modulation of the CAPS-induced currents and the CAPS potentiation of the heat-induced currents. [179]
It is involved in the transduction of the CAPS-binding signal to the opening of the pore and in the 2-APB activation of the channel.
It is also a relevant heat-sensing factor.
K571 E The residue is a specific binding site for 2-APB. [172, 179, 191, 196]
It is involved in voltage sensing and in TRPV1-lipid interactions.
R575 A The residue is involved in voltage sensing and in TRPV1-lipid interactions. [172, 191, 196]
D576 N, R The residue is involved in the voltage-dependent gating of TRPV1, and contributes to the voltage modulation of the CAPS-induced currents and the CAPS potentiation of the heat-induced currents. [179]
It contributes to the transduction of the CAPS-binding signal to the opening of the pore.
R579 A, D, E The residue contributes to the voltage modulation of the CAPS-induced currents and to the CAPS potentiation of heat-induced currents. It is involved in the voltage sensing and in TRPV1-lipid interactions. Its mutation decreased the cholesterol response of the channel. [172, 179, 191, 196, 208]
M581 T The residue contributes to the transduction of the CAPS-binding signal to the opening of the pore, and to the deactivation gating process. It is involved in voltage gating. [177, 179]
Its mutation caused gain of function of the channel and strong toxicity when expressed in Saccharomyces cerevisiae.
F582 Q Its mutation decreased the cholesterol response of the channel. [208]
L585 I Its mutation abolished the cholesterol response of the channel. [208]
I599 A Its mutation caused reduced DkTx responses. [207]
E600 A, D, H, K, Q, S, V The residue is involved in the proton potentiation, but not in proton activation. [43, 167]
Its mutation to neutral or positive residues potentiates responses to CAPS or heat, and introduction of a residue with lower pKa decreased the channel sensitivity to CAPS or heat.
D601 N Its mutation reduced the proton-activated currents significantly, without altering the heat- or CAPS-evoked responses, and without eliminating the ability of protons to potentiate the responses to these stimuli. [43]
M609 T, V Its mutation caused gain of function of the channel and strong/weak toxicity when expressed in Saccharomyces cerevisiae. [177]
C616 G The residue is involved in DTT interaction. [78, 112, 207]
C621 G The residue is responsible for the extracellular modulation of TRPV1 by reducing agents. It is involved in DTT interaction. Its mutation and when associated with C616G and C634G significantly reduced DDT potentiation without having any effect on the CAPS, heat or voltage gating of the channel. [78, 112, 207]
N625 D Its mutation caused toxicity when expressed in Saccharomyces cerevisiae. [177]
Y627 A, W The residue contributes to, but do not play a pivotal role in the proton activation. Its mutation enhanced the sensitivity to the acylpolyamine toxins AG489 and AG505. [192, 200]
N628 D, K, R, W The residue plays essential roles in the heat response without affecting the CAPS responses or the desensitization of the channel. It is involved in proton-induced potentiation. Its mutation reduced the heat responses in amplitude and shifted them to higher temperatures, dramatically decreased the sensitivity to the acylpolyamine toxins AG489 and AG505 and caused toxicity when expressed in Saccharomyces cerevisiae. [167, 177, 192, 200, 213]
S629 A The residue contributes to, but do not play a pivotal role in the proton activation. [192]
T633 A, S, V Its mutation eliminated the proton-activated currents while leaving normal responses to CAPS and low pH potentiation. Its mutation exhibited a weaker response to heat in amplitude, however, the thermal activation threshold was unchanged. [192]
C634 G, S, W It is involved in DTT interaction, its mutation and when associated with C616G and C621G significantly reduced DDT potentiation without having any effect on the CAPS, heat or voltage gating of the channel. Its mutation also enhanced the sensitivity to the acylpolyamine toxins AG489 and AG505, and caused toxicity when expressed in Saccharomyces cerevisiae. [78, 112, 177, 200, 207]
E636 Q, W The residue is a specific contributor to the CAPS response without affecting the proton or thermal sensitivity. Its mutation dramatically decreased the sensitivity to the acylpolyamine toxins AG489 and AG505. [43, 165, 200]
F638 W Its mutation enhanced the sensitivity to the acylpolyamine toxins AG489 and AG505. [200]
F640 A, C, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, Y, The residue is critical for heat activation. Its mutation was constitutively active, and caused strong toxicity when expressed in Saccharomyces cerevisiae. Its mutation also enhanced the sensitivity to heat and CAPS, and abolished the proton potentiation of the channel. This mutation affected gating rather than permeation properties of the channel. [177]
T641 S The residue is involved in acid activation and potentiation. Its mutant displayed large constitutive channel activation and caused toxicity when expressed in Saccharomyces cerevisiae. [177]
D646 N, W The residue is a specific contributor to the CAPS response without affecting the proton or thermal sensitivity, and it is engaged in inhibition by RuRed. Its mutation reduced the permeability of divalent cations and dramatically decreased the sensitivity to the acylpolyamine toxins AG489 and AG505. [43, 165, 176, 197, 213]
L647 W Its mutation enhanced the sensitivity to the acylpolyamine toxins AG489 and AG505. [200]
E648 A, Q The residue is a specific contributor to the CAPS response without affecting the proton or thermal sensitivity. Its mutation reduced the proton-activated currents significantly, without altering the heat- or CAPS-evoked responses, and without eliminating the ability of protons to potentiate the responses to these stimuli. [43, 165]
F649 A, W Its mutation caused reduced DkTx responses, and enhanced the sensitivity to the acylpolyamine toxins AG489 and AG505. [198, 200]
T650 S The residue is involved in proton-induced potentiation. Its mutation caused large constitutive channel activation with abolished pH sensitivity. Its mutation caused toxicity when expressed in Saccharomyces cerevisiae. [177]
E651 Q, W The residue is important in pH activation. Its mutation dramatically decreased the sensitivity to the acylpolyamine toxins AG489 and AG505. [43, 192, 200, 213]
N652 D, T The residue plays essential roles in the heat response without affecting the CAPS responses or the desensitization of the channel. Its mutation reduced the heat responses in amplitude and shifted them to higher temperatures. Its mutation also caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [167, 177]
Y653 T The residue plays essential roles in the heat response without affecting the CAPS responses or the desensitization of the channel. Its mutation reduced the heat responses in amplitude and shifted them to higher temperatures. [167]
K656 E, Q Its mutation caused toxicity when expressed in Saccharomyces cerevisiae. [177]
A657 P, W The residue is critical for DkTx binding, its mutation showed loss of DkTx sensitivity. [197]
V658 A The residue is involved in acid potentiation. Its mutation showed a potentiation effect under moderately acidic conditions. Its mutation also caused toxicity when expressed in Saccharomyces cerevisiae. [177]
F659 A, C, E, H, I, K, L, S, T, V, W, Y The residue is involved in proton activation, and is a key integrator of voltage sensing, proton activation and potentiation. Its mutation caused lack of both voltage-dependent proton activation and potentiation, whereas activation by heat or CAPS was preserved. Its mutation caused reduced DkTx responses and caused toxicity when expressed in Saccharomyces cerevisiae. [177, 194, 195, 198, 199]
Y666 A Its mutation resulted in non-functional channel. [175]
I668 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heat-potentiated CAPS currents. [175]
L669 A The residue is involved in heat activation but not in CAPS activation, nor in the heat potentiation of the CAPS currents. [175]
Y671 A The residue might contribute to allosteric coupling between temperature- and CAPS- dependent activation mechanisms. Its mutation affected the heat-induced current responses, lowered the CAPS EC50 value of the channel. Responses to CAPS were not potentiated by heat in the mutant containing channel, in fact CAPS-evoked responses were inhibited by heat. The residue is involved in the regulation of permeability of divalent cations, it gates the access of smaller cations. [169, 175, 176, 178, 197]
I672 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heat-potentiated CAPS currents. [175]
L673 A, I Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. Its mutation also reduced CAPS sensitivity, heat-induced current responses and heat-potentiated CAPS currents. [175, 177]
L674 A Its mutation reduced CAPS sensitivity, heat-induced current responses and heat-potentiated CAPS currents. [175]
L675 A Its mutation reduced CAPS sensitivity and heat-potentiated CAPS currents. [175]
N676 A, F Its mutation influenced the ability of CAPS and RTX to activate TRPV1 without changing the response of the channel to protons. Its mutation to Ala resulted in non-functional channel. [166, 175]
M677 A Its mutation in a triple mutant (N676F/M677A/L678P) influenced the ability of CAPS and RTX to activate TRPV1 without changing the response of the channel to protons. Its mutation alone blunted heat-induced current responses without a significant change of CAPS- or heat-potentiated CAPS currents. [166, 175]
L678 A, P Its mutation influenced the ability of CAPS and RTX to activate TRPV1 without changing the response of the channel to protons. Its mutation also blunted heat-induced current responses, with a leftward shift in the temperature threshold. [166, 175]
I679 A Its mutation retained normal sensitivities to CAPS and heat, although it completely removed their mutual potentiation. [175]
L681 A The residue is involved in the regulation of permeability of divalent cations, it regulates the permeability of large cations. [169, 175, 178]
M682 A Its mutation caused impaired CAPS- and heat- activation, and significantly reduced their mutual potentiation. [175]
E684 G, V Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. Its mutation caused significant response to pH 6.4 (threshold concentration for proton-activation). [177]
I689 V Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
K694 A The residue participates in PIP2 binding. [206]
K698 A The residue participates in PIP2 binding. [206]
Q700 A The residue participates in PIP2 binding. [206]
R701 A The residue participates in PIP2 binding. [191, 206]
T704 I The residue is a CaMKII phosphorylation site. PMA decreases the binding of [3H]RTX to TRPV1 through interaction with this residue. When associated with S502A, its mutation lost the ability to be activated by CAPS and lost the ability of vanilloid binding. [46, 85, 91, 115, 174]
K710 A, R The residue participates in PIP2 binding. Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [177, 191, 206]
Q727   The residue has key roles in heat activation. [191]
F742 S Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [177]
W752   The residue has key roles in heat activation. [191]
E761 K, Q, Δ Its deletion or mutation blocks RTX binding and proton- and CAPS-induced currents without affecting TRPV1 activation by heat. [16, 175, 176]
K770 A The residue participates in PIP2 binding. [206]
R771 A The residue participates in PIP2 binding. [206]
R778 A The residue has key roles in PIP2 binding. [201, 206]
R781 A The residue has key roles in PIP2 binding. [201, 206]
R785 A The residue participates in PIP2 binding. [201, 206]
W787 R Its mutation caused gain of function and strong toxicity when expressed in Saccharomyces cerevisiae. [177]
L792 P Its mutation caused gain of function mutation and weaker toxicity when expressed in Saccharomyces cerevisiae. Its mutation caused significant response to pH 6.4 (threshold concentration for proton-activation). [177]
L796 P, V Its mutation caused gain of function and strong/weaker toxicity when expressed in Saccharomyces cerevisiae. [177]
S800 A Its phosphorylation by PKC potentiates CAPS, acid, and thermal responses. [78, 85, 209]