INT202526

Context Info Confidence 0.01 First Reported 2007 Last Reported 2007 Negated 1 Speculated 0 Reported most in Body Documents 1 Total Number 8 Disease Relevance 1.77 Pain Relevance 8.31

cell differentiation (ADAM18)

Anatomy Link Frequency neurons 2 ADAM18 (Homo sapiens) ADAM18 - L858F (8)

Pain Link Frequency Relevance Heat Nav1.7 784 99.96 addiction 48 99.92 Pain 88 97.76 dorsal root ganglion 80 97.72 hyperexcitability 8 95.00 sodium channel 80 86.16 nav1.8 32 83.76 Action potential 32 71.04 unmyelinated 8 62.92 Spinal cord 8 58.76

Disease Link Frequency Relevance Heat Pain 88 97.76 Ganglion Cysts 96 97.72 Erythermalgia 216 95.00 Myotonic Disorders 16 22.64 Hypopituitarism 8 9.80 Disease 16 9.52 Muscle Weakness 8 9.32 Heart Arrhythmia 8 7.48 Fever 8 6.80 Arrhythmia Under Development 8 6.68

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

The hyperpolarizing shift in the V1/2 of steady-state activation for L858F compared to WT, at all temperatures tested, is in agreement with our earlier findings [7], and provides a possible explanation for increased excitability in DRG neurons expressing the IEM mutation.

Positive_regulation (activation) of L858F (L858F) in neurons associated with dorsal root ganglion, erythermalgia and nav1.7

1) Confidence 0.01 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0.48 Pain Relevance 0.99

We confirmed a significant hyperpolarizing shift in V1/2 of activation for L858F compared to WT at all three tested temperatures.

Positive_regulation (activation) of L858F (L858F) associated with nav1.7

2) Confidence 0.01 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0 Pain Relevance 0.72

Importantly, steady-state activation of L858F channels is shifted to more depolarized potentials with cooling, whereas the V1/2 of activation for WT channels does not change.

Positive_regulation (activation) of L858F (L858F) associated with nav1.7

3) Confidence 0.01 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0.50 Pain Relevance 1.66

However, a reduction in temperature to 16°C causes a significant shift in a depolarizing direction of the V1/2 of activation of L858F channels, and this shift is not observed for WT channels.

Positive_regulation (activation) of L858F (L858F) associated with nav1.7

4) Confidence 0.00 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0.51 Pain Relevance 0.86

A si</span>milar <span style="background-color:#B0E0E6">increase was observed for L858F: 4.75% ± 0.37% (35°C) and 4.36% ± 0.25% (25°C) to 8.07% ± 0.32% (16°C, Figure 4C).

Positive_regulation (increase) of L858F (L858F)

5) Confidence 0.00 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0 Pain Relevance 0.89

Thus, we </span>speculate that the depolarizing shift in voltage-<span style="background-color:#FFA07A">dependence of activation of L858F Nav1.7 channels at 16°C, which is predicted to decrease DRG neuron excitability, outweighs the effect of the increased ramp currents.

Positive_regulation (activation) of L858F (L858F) in neuron associated with dorsal root ganglion, addiction and nav1.7

6) Confidence 0.00 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0.27 Pain Relevance 1.36

Thus, the relative increase in the ramp current for L858F when cooled from 35°C to 16°C (170%) is smaller than the relative increase for WT (463%; Figure 4C).

Positive_regulation (increase) of L858F (L858F) associated with nav1.7

7) Confidence 0.00 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0 Pain Relevance 1.06

The slope factor of inactivation did not change due to cooling for WT channels, and increases slightly for L858F channels (Figure 3D).

Neg (not) Positive_regulation (increases) of L858F (L858F) associated with nav1.7

8) Confidence 0.00 Published 2007 Journal Mol Pain Section Body Doc Link PMC1781932 Disease Relevance 0 Pain Relevance 0.76

General Comments

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