Capsaicin, acid and heat-evoked currents in rat trigeminal ganglion neurons

Liu, L; Simon, Sidney A.

doi:10.1016/s0031-9384(00)00209-2

Cited by 79 publications

(63 citation statements)

References 68 publications

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“…A large current increase is observed once the temperature reaches a threshold value, near 43°C (vertical (4,6,13). Above T th the current increases by e-fold approximately every 1.3°C, corresponding to a Q 10 of 20.6, similar to sensory neurons (7,8,14). When the temperature of the perfusate was decreased from 48 to 25°C, the current's temperature dependence (I o ) decreased to 5-8°C per e-fold change in current (Fig.…”

Section: Vr1mentioning

confidence: 90%

“…This receptor͞channel is homologous to VR1, but unlike VR1 it can only be activated by thermal stimuli and not by either capsaicin or protons. In single-channel recordings from intact neurons, channels have been identified that are activated by capsaicin but not by acid (pH 5.0) (7,21) or by heat (50°C) (8). Finally, a recent study of VR1 mutants also demonstrates that pore mutations alter the I H ϩ ͞I capsaicin ratio (13).…”

Section: Discussionmentioning

confidence: 99%

“…Although a number of reports have demonstrated the existence of capsaicin receptors in sensory neurons (2,3), the cloning of rat vanilloid receptor 1 (VR1) (4) was a breakthrough in understanding their properties and physiological functions (3,5). VR1 subunits have now been identified in peripheral and central terminals of neurons in sensory ganglia (1,3,4,6,7). Electrophysiological studies of expressed VR1 receptors show that they are activated independently by capsaicin (EC 50 ϭ 0.7 M), acid (pH 50 ϭ 5.4), and elevated temperatures Ն 43°C (3,6).…”

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confidence: 99%

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The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

Welch

Simon²,

Reinhart³

2000

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

180

104

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The recently cloned rat vanilloid receptor, VR1, can be activated by capsaicin, acid, and heat. To determine the molecular mechanisms facilitating channel opening in response to these stimuli, VR1 and six channels containing charge neutralization point mutations surrounding the putative channel pore domain were expressed and characterized in Xenopus laevis oocytes. Steady-state doseresponse relationships, current-voltage relationships, ionic selectivities, and single-channel properties were recorded using voltage-clamp techniques. Three of the mutant channels are significantly more sensitive to capsaicin than is wild-type VR1, whereas none differed in their activation by acidic pH or temperature. Furthermore, one of the mutants has lost all positive cooperativity for capsaicin activation (Hill coefficient Х 1, VR1 Х 2), is much more selective for Ca 2؉ , and exhibits a lower efficacy for acid than for capsaicin activation. Single-channel recordings show that capsaicin-and acid-activated channels have the same conductance, that the three mutants with increased capsaicin sensitivity exhibit higher open probabilities at submaximal capsaicin concentrations, and that the gating properties of capsaicin activation differ from those of acid activation. These data indicate that VR1 undergoes conformational changes upon capsaicin binding that it does not undergo in response to activation by protons or thermal stimuli. Furthermore, these structural rearrangements include the putative pore domain and reveal the location of an intracellular domain that contributes to the positive cooperativity seen for capsaicin activation.C apsaicin, the primary pungent compound in ''hot'' chili peppers, produces pain and inflammation when placed on skin or mucus membranes. These responses are a consequence of capsaicin activating nonselective cation channel receptors within C and A␦ nociceptors and inducing the release of peptides and other transmitters from their peripheral and central terminals (1). Although a number of reports have demonstrated the existence of capsaicin receptors in sensory neurons (2, 3), the cloning of rat vanilloid receptor 1 (VR1) (4) was a breakthrough in understanding their properties and physiological functions (3, 5). VR1 subunits have now been identified in peripheral and central terminals of neurons in sensory ganglia (1,3,4,6,7). Electrophysiological studies of expressed VR1 receptors show that they are activated independently by capsaicin (EC 50 ϭ 0.7 M), acid (pH 50 ϭ 5.4), and elevated temperatures Ն 43°C (3, 6). These conditions are similar to those found in some physiological states (2,3,8). Further findings were that two or more of these activation pathways can act in concert to increase the sensitivity of VR1 receptors to any one stimulus (6,8). To determine protein domains important for the activation of VR1 by capsaicin, protons, and heat, we constructed a number of VR1 point mutants and measured their responsiveness to these three activators. We found that mutations near the pore of VR1 channels ca...

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Section: Vr1mentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

Welch

Simon²,

Reinhart³

2000

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

180

104

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“…6). Under these conditions, the percentage blockage is not dependent on the voltage (see I Ap -V plots) even though the I-V relation of capsaicin-activated currents is strongly voltage dependent (Liu and Simon 2000), suggesting that the capsaicin-induced currents do not markedly contribute to the blockage. Finally, after washing these cells for another 3-6 min, the I A currents recovered (78.7 Ϯ 21.2% n ϭ 12) to their precapsaicin values.…”

Section: K and I A Currents In Tg Neuronsmentioning

confidence: 90%

Modulation of I _A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

Liu

Simon

2003

Journal of Neurophysiology

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Liu, L., and S. A. Simon. Modulation of I A currents by capsaicin in rat trigeminal ganglion neurons. J Neurophysiol 89: 1387-1401, 2003; 10.1152/jn.00210.2002. When capsaicin, the pungent compound in hot pepper, is applied to epithelia it produces pain, allodynia, and hyperalgesia. We investigated, using whole cell path clamp, whether some of these responses induced by capsaicin could be a consequence of capsaicin blocking I A currents, a reduction in which, such as occurs in injury, increases neuronal excitability. In capsaicin-sensitive (CS) rat trigeminal ganglion (TG) neurons, capsaicin inhibited I A currents in a dose-dependent manner. I A currents were reduced 49% by 1 M capsaicin. In capsaicin-insensitive (CIS) rat TG neurons, or smalldiameter mouse VR1Ϫ/Ϫ neurons, 1 M capsaicin inhibited I A currents 9 and 3%, respectively. These data suggest that in CS neurons the vast majority of the capsaicin-induced inhibition of I A currents occurs as a consequence of the activation of vanilloid receptors. Capsaicin (1 M) did not alter the I A conductance-voltage relationship but shifted the inactivation-voltage curve about 15 mV to hyperpolarizing voltages, thereby increasing the number of inactivated I A channels at the resting potential. I A currents were relatively unaffected by 1 mM CTP-cAMP or 500 nM phorbol-12, 13-dibuterate (a protein kinase C agonist) but were inhibited by 20 -30% with either 1 mM CTP-cGMP or 25 M N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide HCl (a calcium-calmodulin kinase inhibitor). In the presence of 0.5 M KT5823, an inhibitor of protein kinase G (PKG) pathways, 1 M capsaicin inhibited I A by only 26%. In summary, in CS neurons, capsaicin decreases I A currents through the activation of vanilloid receptors. That activation, partially through the activation of cGMP-PKG and calmodulin-dependent pathways should result in increased excitability of capsaicin-sensitive nociceptors.

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“…Also, capsaicin, the primary pungent compound in hot pepper, evokes changes in [Ca 2ϩ ] i in sensory neurons by activation of the transient receptor potential vanilloid 1 (TRPV1) (15)(16)(17). These compounds, as well as other neurotransmitters and chemicals, have been shown to evoke intracellular acidification through an increase in [Ca 2ϩ ] i in sensory neurons (2,18).…”

mentioning

confidence: 99%

Intracellular Acidification Is Associated with Changes in Free Cytosolic Calcium and Inhibition of Action Potentials in Rat Trigeminal Ganglion

Hwang

Koo²,

Jin³

et al. 2011

Journal of Biological Chemistry

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Capsaicin, acid and heat-evoked currents in rat trigeminal ganglion neurons

Cited by 79 publications

References 68 publications

The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

Modulation of I _A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

Intracellular Acidification Is Associated with Changes in Free Cytosolic Calcium and Inhibition of Action Potentials in Rat Trigeminal Ganglion

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Capsaicin, acid and heat-evoked currents in rat trigeminal ganglion neurons

Cited by 79 publications

References 68 publications

The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat

Modulation of I A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons

Intracellular Acidification Is Associated with Changes in Free Cytosolic Calcium and Inhibition of Action Potentials in Rat Trigeminal Ganglion

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Modulation of I _A Currents by Capsaicin in Rat Trigeminal Ganglion Neurons