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Review
. 1999 Jul 6;96(14):7658-63.
doi: 10.1073/pnas.96.14.7658.

Ion channels gated by heat

P Cesare  1 , A Moriondo, V Vellani, P A McNaughton
Affiliations
Review

Ion channels gated by heat

P Cesare et al. Proc Natl Acad Sci U S A. .

Abstract

All animals need to sense temperature to avoid hostile environments and to regulate their internal homeostasis. A particularly obvious example is that animals need to avoid damagingly hot stimuli. The mechanisms by which temperature is sensed have until recently been mysterious, but in the last couple of years, we have begun to understand how noxious thermal stimuli are detected by sensory neurons. Heat has been found to open a nonselective cation channel in primary sensory neurons, probably by a direct action. In a separate study, an ion channel gated by capsaicin, the active ingredient of chili peppers, was cloned from sensory neurons. This channel (vanilloid receptor subtype 1, VR1) is gated by heat in a manner similar to the native heat-activated channel, and our current best guess is that this channel is the molecular substrate for the detection of painful heat. Both the heat channel and VR1 are modulated in interesting ways. The response of the heat channel is potentiated by phosphorylation by protein kinase C, whereas VR1 is potentiated by externally applied protons. Protein kinase C is known to be activated by a variety of inflammatory mediators, including bradykinin, whereas extracellular acidification is characteristically produced by anoxia and inflammation. Both modulatory pathways are likely, therefore, to have important physiological correlates in terms of the enhanced pain (hyperalgesia) produced by tissue damage and inflammation. Future work should focus on establishing, in molecular terms, how a single ion channel can detect heat and how the detection threshold can be modulated by hyperalgesic stimuli.

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Figures

Figure 1
Figure 1
Depolarization and a train of action potentials initiated in a nociceptive neuron in culture by application of a brief heat stimulus. Membrane potential recorded by using whole-cell patch clamp (see ref. for details).
Figure 2
Figure 2
Responses of membrane current in isolated nociceptors to heat. (A) Application of a rapid step change in temperature (from room temperature to 49°C; time course shown by the top trace) elicits an inward current with a short delay (≈35 ms) in a nociceptive neuron (lower of the two membrane current traces). In heat-insensitive neurons, a much smaller current change is elicited with no delay (top current trace). Neurons were voltage-clamped by the whole-cell patch-clamp method at −70 mV. (B). Current as a function of temperature in a heat-sensitive neuron (lower trace) and in a heat-insensitive neuron (upper trace). Modified from ref. .
Figure 3
Figure 3
Noise associated with opening of heat-activated ion channels. (A) Examples of cell-attached patch-clamp recordings of the responses of a heat-insensitive neuron (top recording) and a heat-sensitive neuron (bottom recording) to temperature steps. Patch pipette contained only 154 mM NaCl/10 mM Hepes to maximize current through heat-sensitive ion channels and was held at 0 mV. Heat-sensitive currents through channels outside the patch were prevented by bathing the rest of the cell in solution free of permeant ions (154 mM N-methyl glucamine/10 mM Hepes). (B) Power spectrum of cell-attached current activated by a temperature step to 49°C. For each experiment, 10 consecutive traces (16,384 samples per trace at 10 kHz; filtered at 4 kHz) were acquired, first at room temperature then at 49°C, and the power spectra were calculated. Heat-induced power spectrum (points) was calculated as the difference between the two spectra. Power spectrum fitted with the sum of two Lorentzian functions (sum shown as a solid line; component spectra as a dashed line) with half-power frequencies as shown, corresponding to time constants of 17 ms and 0.49 ms (V.V., P.C., and P.A.M., unpublished data).
Figure 4
Figure 4
Phosphorylation by PKC sensitizes the heat response of nociceptors. (A) Response of membrane current to a 49°C heat pulse before and after exposure to bradykinin (Bk). (B) Similar effect to that seen in A is observed after treatment by the specific PKC activator phorbol myristate acetate (PMA). (C) Current vs. temperature relations before and after PMA treatment, showing sensitization of the heat response. [Reproduced with permission from ref. (Copyright 1996, Proceedings of the National Academy of Sciences of the United States of America)].
Figure 5
Figure 5
The heat-sensitive current in a nociceptor undergoes desensitization in response to a maintained pulse of heat (P.C., A.M., V.V., and P.A.M., unpublished data).
Figure 6
Figure 6
Possible model for sensitization of the heat response. Acidification of the external solution causes protonation of an external site on the heat-sensitive ion channel and consequent sensitization (19). Phosphorylation at the internal surface has a similar effect (6). Both effects are reversible. PP, phosphatase.
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