Abstract
In this chapter we discuss the polymodal activation of thermo-TRP channels using as exemplars two of the best characterized members of this class of channels: TRPM8 and TRPV1. Since channel activation by temperature is the hallmark of thermo-TRP channels, we present a detailed discussion on the thermodynamics involved in the gating processes by temperature, voltage, and agonists. We also review recently published data in an effort to put together all the pieces available of the amazing puzzle of thermo-TRP channel activation. Special emphasis is made in the structural components that allow the channel-forming proteins to integrate such diverse stimuli, and in the coupling between the different sensors and the ion conduction pathway. We conclude that the present data is most economically explained by allosteric models in which temperature, voltage, and agonists act separately to modulate channel activity.
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Notes
- 1.
TM: Transmembrane domain, helixes spanning the lipid bilayer membrane.
- 2.
In the TRPV subfamily the signature sequence is TIGX1GX2 (X1 = M or L; X2 = D or E) for TRPV1-4 and FLTXID (X = V or I) for TRPV5-6.
- 3.
Temperature coefficient. Is a measure of the kinetic reaction change of a system as a consequence of increasing the temperature by 10ºC. Q10 is a useful parameter to establish temperature dependence of a process. the Q10 could be easily obtained from the macroscopic currents using the following definition:
$$ \ Q_{10} = \left( {\frac{{I_2 }}{{I_1 }}} \right)^{\tfrac{{10}}{{(T_2 - T_1 )}}} ,$$where I 1 and I 2 are the currents obtained at temperatures, T 1 and T 2 . Although the Q10 obtained by this procedure is very useful as a comparative value it lacks thermodynamic meaning. A relationship between Q10 and the Arrhenius activation energy (E a ) can be obtained by measuring rate constants, k, at different temperatures since k = Aexp(-Ea/RT) where A is a constant called the frequency factor [28]. It is easy to show that
$$E_a = R\left( {\frac{{T_1 T_2 }}{{T_2 - T_1 }}} \right)\ln \frac{{k_2 }}{{k_1 }},$$where k 1 and k 2 are the time constants measured at T 1 and T 2 , respectively that can be written as:
$$E_a = - RT_1 \left( {\frac{{T_1 + 10}}{{10}}} \right)\ln Q_{10},$$ - 4.
- 5.
Threshold: In general this concept should avoided in particular considering that in ion channels the average state of activation is governed by a probability distribution that does not resemble an “all or none” process typical of action potentials. In thermo-TRP, this concept must be understood as a characteristic temperature at which the channel activity is significant at a given voltage and/or agonist concentration.
- 6.
Burst: Single channel gating, where the channel activity is grouped in periods of high activity, flanked by gaps or quiescent periods.
- 7.
PKC: Protein Kinase C, protein that mediate S/T phosphorylations in a Ca+2 dependent manner.
- 8.
2-APB: 2-aminoethoxydiphenyl borate, agonist of TRPV1 channel
- 9.
FRET: Förster Resonance Energy Transfer, this technique uses the non radiative energy transfer between two chromophores. The efficiency of the transfer process is very sensitive to the distance and is used to establish conformational changes in proteins.
- 10.
MCD binds cholesterol reversibly and is commonly used to deplete membrane cholesterol acutely from both leaflets of the bilayer [61].
- 11.
TRP Box is a consensus sequence, IWKLQR, located in C-terminal of the TRP channels.
- 12.
MWC: Monod, Wyman and Changeux allosteric model or concerted model. This model explain transitions between symmetrical subunits that can bind agonist in an independent way, changing the subunit from relaxed to activated states.
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Acknowledgments
We thanks Dr. Giulio Vistoli for kindly providing us with the PDB of the structure of the TRPM8 channel and to Dr. Fernando González-Nilo for much help and advice in TRP channel modelling. Supported by grant from the Fondo Nacional de Investigación Científica, FONDECYT 1070049.
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Baez-Nieto, D., Castillo, J.P., Dragicevic, C., Alvarez, O., Latorre, R. (2011). Thermo-TRP Channels: Biophysics of Polymodal Receptors. In: Islam, M. (eds) Transient Receptor Potential Channels. Advances in Experimental Medicine and Biology, vol 704. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0265-3_26
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