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Journal of Physiology (2002), 545.1, pp. 43-50
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.027656
2/neurturin signalling regulates noxious heat transduction in isolectin B4-binding mouse sensory neurons |
ABSTRACT |
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The GFR
(Received 28 June 2002; accepted after revision 1 October 2002; first published online 18 October 2002)
Corresponding author G. R. Lewin: Growth Factors and Regeneration Group, Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert- Rössle Str. 10, D-13092 Berlin, Germany. Email: glewin{at}mdc-berlin.de
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INTRODUCTION |
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Nociceptive sensory neurons with unmyelinated axons (C fibres) have been divided into two distinct classes on the basis of their neurochemical, anatomical and functional properties (Snider & McMahon, 1998; Stucky & Lewin, 1999). One group expresses a surface carbohydrate group that binds the plant lectin isolectin B4 (IB4) but expresses relatively few neuropeptides. The second group does not bind IB4 but is rich in expression of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (Snider & McMahon, 1998). Sensory neurons that bind IB4 acquire a dependence on glial cell line-derived neurotrophic factor (GDNF) for survival in the immediate postnatal period and lose their receptors for the more classical neurotrophin nerve growth factor (NGF) (Molliver et al. 1997). GDNF and the related molecule neurturin (NRTN) exert their actions by binding to the glycosyl phosphatidyl inositol (GPI)-anchored receptors GFR 1 and GFR 2, respectively, and these receptors together with their respective ligands then form signalling receptor complexes with the common transmembrane re-arranged in transformation (RET) tyrosine kinase (Baloh et al. 2000). GFR 1, GFR 2 and RET receptors are expressed extensively by the IB4-binding GDNF-dependent population but are virtually absent in the trkA-expressing NGF-dependent nociceptors. The GFR 2 receptor in particular is tightly co-localized with the IB4-positive class of nociceptors as nearly 80 % of GFR2-expressing neurons bind IB4 (Bennett et al. 1998).
The fact that GFR 2 expression overlaps extensively with the IB4-positive population of nociceptors suggested to us that GFR 2 in combination with RET may regulate functional properties of these nociceptors. Approximately one-half of IB4-positive nociceptors are normally sensitive to noxious heat (Stucky & Lewin, 1999) and many are sensitive to noxious mechanical stimuli (Gerke & Plenderleith, 2001; Vulchanova et al. 2001). Therefore, we studied the thermal and mechanosensitive functional properties of small-diameter sensory neurons in mice with a targeted disruption of GFR 2 (Rossi et al. 1999). We found that endogenous signalling via the GFR 2 receptor is specifically required to sustain noxious heat sensitivity in IB4-positive nociceptors but is not required for the survival of these neurons or any other class of cutaneous sensory neurons. Furthermore, our results indicate that GFR 2 receptor/NTRN signalling plays a classical trophic role in the maintenance of axon diameter.
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METHODS |
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Neuronal cultures
Adult mice heterozygous for deletion of the GFR 2 receptor were bred and genotyped as previously described (Rossi et al. 1999), and adult GFR 2 -/- and GFR 2 +/+ offspring were used for this study. Animal housing and killing, and all experiments were carried out according to the German national guidelines. To analyse noxious heat currents in sensory neurons, GFR 2 +/+ (n = 5) and GFR 2 -/- (n = 6) mice were rapidly killed by inhalation of a rising concentration of CO2. Dorsal root ganglia (DRG) from all spinal levels were removed and incubated with 1 mg ml-1 collagenase IV (Sigma) for 30 min at 37 °C followed by 0.05 % trypsin (Sigma) for 30 min at 37 °C. DRGs were resuspended in DMEM/Ham's F12 media supplemented with 10 % heat-inactivated horse serum (Biochrom, UK), 20 mM glutamine, 0.8 % glucose, 100 units penicillin and 100 mg ml-1 streptomycin (Gibco). DRGs were dissociated into single cells by passing them through fire-polished Pasteur pipettes of decreasing diameter, spot-plated on poly-L-lysine (200 mg ml-1)-coated coverslips at a density of 1000-2000 cells per coverslip and maintained at 37 °C in 5 % CO2. The median time in culture was 24 h (range 4-48 h). An approximately equal number of IB4-positive and -negative neurons were recorded on each experimental day.
Electrophysiology
Whole cell electrophysiological recordings were made using fire-polished, glass electrodes of 3-5 M
resistance pulled from borosilicate glass (Hilgenberg, Malsfeld, Germany) on a laser micropipette puller (P-2000, Sutter Instrument Co., Novato, CA, USA). The recording chamber (volume 500 µl) containing a coverglass with adherent neurons was continuously superfused (2-3 ml min-1) with extracellular solution containing (mM): NaCl, 154; KCl, 5.6; CaCl2, 2; MgCl2, 1; Hepes, 10; glucose, 8. pH was adjusted to 7.4 with NaOH and osmolarity was adjusted to 325 mosmol l-1 with sucrose. The electrodes were filled with solution containing (mM): KCl, 122; Na+, 10; MgCl2, 1; EGTA, 1; Hepes, 10. pH was adjusted to 7.3 with KOH and osmolarity was adjusted to 290 mosmol l-1 with sucrose. Neurons were visualized using phase contrast illumination at 
63 magnification on a Leica DMIRB inverted microscope. The diameter of each neuron was calculated from the mean of the longest and shortest diameters measured with a calibrated reticule. Only small-diameter neurons (< 26 µm), which are predominantly unmyelinated nociceptors, were used (Stucky & Lewin, 1999). For heat tests, temperature in the recording bath was monitored using a miniature thermocouple (response time constant of 5 ms; Physitemp, Clifton, NJ, USA) placed 1 mm from the recorded neuron. Heat ramp stimuli (from 24 to 49 °C in 10 ± 1 s) were applied by heating the extracellular solution immediately before it entered the bath. Bath temperature was maintained at room temperature (22-24 °C) except during heat tests. One neuron per coverglass was characterized and after each recording, neurons on the coverglass were incubated with 10 µg ml-1 IB4 conjugated directly to fluorescein isothiocyanate (IB4-FITC) for 10 min and then rinsed for 5 min in normal extracellular solution.
Data recording and analysis
Membrane voltage or current was clamped using an EPC-9 amplifier run by Tida 4.1 software for Windows 95 (HEKA Electronic, Lambrecht, Germany). Data were filtered using a 4-pole Bessel filter (5.0 kHz) and sampled at 20 kHz. Whole cell configuration was maintained at a holding potential of -60 mV. Seals ranged from 1.5 to 6.0 G. Neurons were discarded if they did not exhibit an action potential overshoot, had resting potentials more positive than -45 mV in current clamp mode, or exhibited a reduction in magnitude of whole cell inward currents greater than 20 % after a heat test. For generating a family of whole cell voltage currents, neurons were pre-pulsed to -120 mV for 150 ms and then depolarized from -50 to +50 mV in increments of 5 mV (40 ms for each depolarizing test pulse). Voltage errors were minimized by using 70 % series resistance compensation, and pipette and cell capacitance artifacts were cancelled by using the computer-controlled circuitry of the patch clamp amplifier. For generation of action potentials (APs), currents from 0.02 to 1.2 nA were injected for 40 ms at each step. AP threshold was taken as the lowest current injected that evoked an AP with an overshoot. The duration of the AP was taken between 50 % and 75 % of the peak amplitude from resting potential because the 50 % amplitude was close to the base of the AP whereas 75 % was near the inflection on the falling phase of the AP.
IB4 staining of fixed cultures
Cultures of neurons from adult wild-type (n = 3) and GFR 2 (n = 3) mutant mice were prepared and fixed 24 h after isolation with 4 % paraformaldehyde for 20 min. Neurons were incubated with 10 mg ml-1 FITC-labelled IB4 in 0.1 M PBS containing 0.1 mM CaCl2, 0.1 mM MgCl2 and 0.1 mM MnCl2 for 1 h and then rinsed and inverted on a slide over a drop of Mowiol. Openlab software (Improvision, UK) was used for analysis. Images of fields of cells (6 fields per culture) were randomly collected at a magnification of 20. A total of 645 neurons were analysed for mean brightness intensity and mean soma diameter. To determine non-specific staining per culture, brightness intensities were sampled and averaged from six large-diameter neurons that were clearly negative for IB4. Our previous results show that the largest IB4-positive neurons from adult mouse are 26 µm in diameter (Stucky & Lewin, 1999). Neurons with staining intensities 40 % or more above this value were considered IB4 positive.
Skin-nerve preparation
Mice were rapidly killed by inhalation of a rising concentration of CO2 and the hindlimb was shaved. The skin from the territory innervated by the saphenous nerve, a purely cutaneous nerve, was removed with the nerve intact. The preparation was placed in an organ bath and superfused with an oxygen-saturated modified interstitial fluid solution containing (mM): NaCl, 123; KCl, 3.5; MgSO4, 0.7; NaH2PO4, 1.7; CaCl2, 2.0; sodium gluconate, 9.5; glucose, 5.5; sucrose, 7.5; Hepes, 10 (pH 7.4 + 0.05); temperature, 32 ± 0.5 °C. Recordings were made from functionally single myelinated fibres in teased filaments of the nerve and characterized according to previously described criteria (Koltzenburg et al.1997).
Nerve histology
The saphenous nerve from wild-type (n = 4) and GFR 2 mutant (n = 4) mice was exposed at mid-thigh level, fixed with 2.5 % glutaraldehyde in 0.15 M PB for 10 min and a 3 mm segment was removed and post-fixed in 2.5 % glutaraldehyde. Nerve segments were then fixed in 1 % OsO4 in 0.1 M cacodylate for 1 h at room temperature, washed in cacodylate buffer, dehydrated in graded alchohols, infiltrated with propylene oxide and embedded in epoxy resin and polymerized at 60 °C for 24 h. Ultrathin sections (0.7-0.8 nm) were cut on an ultramicrotome, stained with lead citrate and uranyl acetate and photographed on an electron microscope. Myelinated and unmyelinated axons were counted using Metamorph image software. For myelinated axons, the entire nerve cross-section was counted; for unmyelinated axons, a sample of the nerve was analysed and extrapolated to determine the total number of axons in each nerve.
For statistical measures in all experiments, groups were compared using a two-tailed, unpaired t test or Fisher's exact test. All error bars shown represent the standard error of the mean (S.E.M.).
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RESULTS |
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The responsiveness of isolated small-diameter (< 26 µm) sensory neurons to noxious heat was measured using whole cell patch clamp methods. Immediately after recordings, neurons were identified as IB4-positive or -negative by using a fluorescent-tagged isolectin B4. Noxious heat-induced inward current was measured in 110 isolated small-diameter (< 26 µm) dorsal root ganglion neurons from GFR 2 -/- mice and GFR 2 +/+ controls. Figure 1A shows noxious heat-evoked inward current in an IB4-positive and an IB4-negative small-diameter neuron from a wild-type mouse. The percentage of IB4-negative neurons that responded to noxious heat with a large inward current > 100 pA was normal in GFR 2 -/- mice (47 % 16/34) compared to GFR 2 +/+ littermates (38 % 9/24) (Fig. 1B). In contrast, only 12 % (4/33) of IB4-positive neurons from GFR 2 -/- mice exhibited a heat-evoked inward current larger than 100 pA compared to 47 % (9/19) from GFR 2 +/+ mice (P = 0.008; Fisher's exact test). Figure 1C shows that the decrease in the number of IB4-positive neurons with heat currents larger than 100 pA was due to a shift in more neurons with smaller heat currents (< 100 pA) as well as to an increase in neurons with no detectable heat current (0 pA). Other properties of IB4-positive and -negative neurons from GFR 2 -/- mice including heat threshold, cell diameter, capacitance, input resistance and amplitude, duration and threshold of the somal action potential were not different from wild-type controls (data not shown).
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Figure 1. IB4-positive neurons with large heat currents are markedly reduced in GFR A, examples of noxious heat-induced inward currents in an IB4-positive and an IB4-negative neuron from a wild-type mouse. B, the percentage of IB4-positive neurons with heat-evoked currents > 100 pA was substantially reduced in GFR | ||
To determine whether the loss of IB4-positive neurons with large magnitude heat-evoked currents was due to selective death of these neurons in GFR 2 -/- mice, we counted the number of unmyelinated fibres in the saphenous nerve as previously described (Stucky et al. 1999). There was no loss in the number of unmyelinated axons in GFR 2 mutant mice (2899 ± 428; n = 4) compared to wild-type littermates (2868 ± 246; n = 4), indicating that the axons of the unmyelinated IB4-positive neurons were present in normal numbers. There was also no change in the number of myelinated axons in the mutant mice (531 ± 32; n = 4) compared to controls (542 ± 15; n = 4).
Interestingly, however, the diameter of the entire saphenous nerve was smaller in GFR 2 -/- mice (Fig. 2A and B), and this was due to the finding that the individual axon diameters of both unmyelinated and myelinated axons were significantly smaller in GFR 2 -/- mice (Fig. 2C and D). The mean diameter of unmyelinated axons in GFR 2 -/- mice was only 0.45 ± 0.00 µm compared to 0.70 ± 0.00 µm in wild-type littermates (P < 0.001; t test), and the diameter of myelinated axons in GFR 2 -/- mice was 3.10 ± 0.03 µm compared to 3.76 ± 0.03 µm in wild-type controls (P < 0.001; t test). These findings indicate that GFR 2/neurturin signalling plays a classic neurotrophic factor role in regulating axon diameter, particularly for the unmyelinated axons from GFR 2 -/- mice which showed a substantial shift to the left in Fig. 2C.
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Figure 2. GFR A and B, cross-sections of the saphenous nerve at mid-thigh level from a wild-type (A) and a GFR | ||
Furthermore, if the reduction in the number of IB4-positive neurons with large heat currents was due to selective cell death, one would expect that a significant proportion of IB4-positive neurons would be missing. Therefore, we quantified the proportion of small-diameter neurons that were positive for IB4 among the total neurons isolated from the ganglia. We found no indication that there was a selective loss of IB4-positive neurons, as the percentage of IB4-positive neurons present in short term cultures of isolated dorsal root ganglion neurons from GFR 2 -/- mice (48.8 %; n = 3 animals) was identical to that in wild-type mice (48.8 %; n = 3 animals) (Fig. 3A and B). Unlike the decreased axon diameter of all axons in GFR 2 -/- mice, the average soma diameter of DRG neurons from these mice was not different from controls (IB4 positive: 20.0 ± 0.4 µm in GFR 2 -/- (n = 125) vs. 20.3 ± 0.4 µm in GFR 2 +/+ (n = 190); IB4 negative: 24.3 ± 0.8 µm in GFR 2 -/- (n = 131) vs. 22.8 ± 0.6 µm in GFR 2 +/+ (n = 199)). Together, our results indicate that the GFR 2 receptor is required for setting the heat sensitivity of IB4-positive neurons but the receptor is not required at any time in development for their survival.
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Figure 3. GFR A-B, histograms illustrate the distribution of cell bodies of IB4-positive and -negative neurons in DRG cultures taken from GFR | ||
Because heat sensitivity depends on the presence of GFR2, we then determined whether the GFR 2 receptor is also required for other functional modalities besides heat. Since over 80 % of cutaneous sensory neurons, including IB4-positive nociceptors, are responsive to mechanical stimuli (Kress et al. 1992; Gerke & Plenderleith, 2001; Vulchanova et al. 2001), we determined whether the absence of the GFR 2 receptor affects mechanotransduction. The in vitro skin nerve preparation is particularly well-suited for testing the mechanical responsiveness of the terminals of cutaneous afferents in situ (Koltzenburg et al. 1997). Thus, we used this approach and recorded from 178 cutaneous sensory neurons in GFR 2 -/- and GFR 2 +/+ mice and found that all subtypes of cutaneous neurons with myelinated axons were present in normal numbers and had normal mechanical response properties (Table 1). Large-diameter, low-threshold mechanoreceptors (A
fibres), which are classified as either slowly adapting (SA) or rapidly adapting (RA) were encountered with a normal frequency and their mechanosensitivity in GFR 2 -/- mice was indistinguishable from SA and RA fibres recorded in GFR 2 +/+ wild-type littermates (Table 1). Similarly, small-diameter, thinly myelinated mechanoreceptors (A
fibres), which are classified as either A-fibre myelinated nociceptors (AM) or down-hair follicle receptors (D-hairs), were unaffected in GFR 2 -/- mice. The finding that all four classes of myelinated fibres were functionally normal in GFR 2 mutants is consistent with evidence that myelinated sensory neurons largely do not express mRNA for the GFR 2 receptor (Bennett et al. 1998).
Since approximately one-half of the unmyelinated C fibres (the IB4-binding population) do express GFR 2, we examined the mechanical responsiveness of C fibres and found that the mechanical von Frey thresholds and the maximum action potential discharge (not shown) were unaltered in the GFR 2 mutants (Table 1). Therefore, the absence of GFR 2 has a modality-specific effect on heat transduction in unmyelinated nociceptors. Surprisingly, in spite of the smaller diameter of both unmyelinated and myelinated axons from GFR 2 -/- mice, there was no significant slowing in the conduction velocity of any subclass of these fibres in GFR 2 -/- mice (Table 1).
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DISCUSSION |
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The major findings in our study are: (1) the GFR 2 co-receptor which preferentially binds neurturin is required for the proper function of a heat transducer that is specifically localized to IB4-positive nociceptors; (2) whereas the GFR 2 receptor is necessary for heat transduction, it is not required for the survival of these IB4-positive neurons, nor is it essential for the survival of any other functionally or neurochemically defined class of cutaneous sensory neurons; (3) the GFR 2-mediated regulation of heat transduction is modality specific because the mechanical response properties of unmyelinated C fibres, including those responsive to GDNF family ligands, were unaffected in the absence of GFR 2. Furthermore, the mechanical function of all other subtypes of cutaneous sensory neurons was completely normal in the absence of GFR 2.
GFR 2 receptor signalling regulates heat transduction in IB4-positive nociceptors
Our results clearly show that GFR 2 signalling is necessary for the large-magnitude heat responses in IB4-positive unmyelinated nociceptors. The finding that the effect on heat transduction is localized to IB4-positive nociceptors is consistent with evidence that GFR 2 and RET receptors are expressed specifically by one-half of the small-diameter neurons that bind IB4 (Molliver et al. 1997; Bennett et al. 1998) and by our previous studies showing that 50 % of IB4-positive neurons respond to noxious heat (Stucky & Lewin, 1999; Pesquero et al. 2000).
The ligand that binds to the GFR 2 co-receptor and, together with RET, regulates the heat responsiveness of IB4-positive nociceptors is most likely to be neurturin (NRTN). Among the GDNF family ligands, NRTN has the highest selectivity for GFR 2, although GDNF at high concentrations has also been shown to activate GFR 2 (Heuckeroth et al. 1999; Rossi et al. 1999; Baloh et al. 2000). In addition, we previously showed that exogenous GDNF has no effect on the heat responsiveness of IB4-positive nociceptors (Stucky & Lewin, 1999), a result that is consistent with the hypothesis that NTRN but not GDNF is probably the ligand that mediates the effect of GFR 2 on heat transduction.
The heat receptor that mediates the large heat-evoked inward currents in IB4-positive neurons and that requires GFR 2 signalling may be the vanilloid receptor-1 (VR1). VR1 is abundantly expressed in nociceptors and confers heat responsiveness to isolated cells (Caterina et al. 1997, 2000). Furthermore, evidence shows that neurotrophic factors can regulate VR1 because NGF rapidly sensitizes DRG neurons to capsaicin (Shu & Mendell, 1999, 2001), possibly by NGF/trkA releasing VR1 from phosphotidylinositol-mediated inhibition (Chuang et al. 2001). However, other lines of evidence suggest that non-VR1 heat receptors may be involved. First, only 2-3 % of IB4-positive neurons in mouse appear to stain with VR1 antibodies (Zwick et al. 2002), even though 45-50 % of IB4-positive neurons respond to noxious heat (Stucky & Lewin, 1999). Second, animals lacking VR1 surprisingly retain much of their responsiveness to acute noxious heat, suggesting that heat receptors other than VR1 exist (Caterina et al. 2000; Davis et al. 2000). Indeed, other heat-sensitive ion channel receptors have recently been identified that include TRPV3 and TRPV4 (Güler et al. 2002; Peier et al. 2002; Smith et al. 2002) and TRPV3 has been found in small-diameter sensory neurons (Smith et al. 2002). Our finding that many small-magnitude heat-evoked currents (< 100 pA) remain in IB4-positive neurons from GFR 2 -/- mice suggests that the GFR 2 receptor regulates some but not all of the noxious heat receptors in IB4-positive nociceptors.
GFR 2 receptor signalling is not required for the survival of any subclass of cutaneous sensory neuron
Together, our quantification of the numbers of myelinated and unmyelinated cutaneous axons, IB4-positive and -negative DRG neurons and proportions of functionally classified cutaneous fibres demonstrates that no class of cutaneous sensory neurons depends on GFR 2 signalling for survival during embryonic or postnatal development. This finding is consistent with an earlier report that there is no significant loss (
10 %) in cell soma number in the trigeminal ganglia from GFR 2 -/- mice (Rossi et al. 1999). In addition, a recent study showed that motor neurons depend upon the presence of the GFR 1 receptor but not GFR 2 for survival during development (Garcés et al. 2000). Thus, the survival of both cutaneous and motor neurons during development is independent of GFR 2 signalling.
Although no axons were lost in GFR 2 mutants, the size of the saphenous nerve was notably smaller and the diameters of individual myelinated and unmyelinated axons were significantly smaller. These data indicate that, similar to the actions of other neurotrophins such as NGF and brain-derived neurotrophic factor, GFR 2 signalling plays a classic role in developing or maintaining the axon diameter of cutaneous sensory neurons (Cellerino et al. 1997; Stucky et al. 1999).
Our data identify a novel and specific role for GFR 2 receptor signalling in regulating heat transduction. Since NTRN is the preferred ligand for the GFR 2 receptor, the available data suggest that the target-derived GDNF family ligands play quite different roles in regulating IB4-positive nociceptors. GDNF signalling regulates the postnatal survival of IB4-positive neurons (Molliver et al. 1997; Bennett et al. 1998) whereas NTRN signalling regulates the noxious heat response function of these neurons. In summary, along with pharmaceutical therapies that inhibit NGF/TrkA-mediated sensitization of IB4 negative, peptidergic nociceptors (Shu & Mendell, 1999, 2001; Heppenstall & Lewin, 2000), it may be appropriate to consider the neurturin-GFR 2-RET signalling pathway as a potential target for analgesic therapy.
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REFERENCES |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
| BALOH, R. H., ENOMOTO, H., JOHNSON, E. M. JR & MILBRANDT, J. (2000). The GDNF family ligands and receptors - implications for neural development. Current Opinion in Neurobiology 10, 103-110 | [Medline] |
| BENNETT, D. L., MICHAEL, G. J., RAMACHANDRAN, N., MUNSON, J. B., AVERILL, S., YAN, Q., MCMAHON, S. B. & PRIESTLEY, J. V. (1998). A distinct subgroup of small DRG cells express GDNF receptor components and GDNF is protective for these neurons after nerve injury. Journal of Neuroscience 18, 3059-3072 | [Abstract/Full Text] |
| CATERINA, M. J., LEFFLER, A., MALMBERG, A. B., MARTIN, W. J., TRAFTON, J., PETERSEN-ZEITZ, K. R., KOLTZENBURG, M., BASBAUM, A. I. & JULIUS, D. (2000). Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306-313 | |
| CATERINA, M. J., SCHUMACHER, M. A., TOMINAGA, M., ROSEN, T. A., LEVINE, J. D. & JULIUS, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816-824 | [Medline] |
| CELLERINO, A., CARROLL, P., THOENEN, H. & BARDE, Y. A. (1997). Reduced size of retinal ganglion cell axons and hypomyelination in mice lacking brain-derived neurotrophic factor. Molecular and Cellular Neuroscience 9, 397-408 | |
| CHUANG, H., PRESCOTT, E. D., KONG, H., SHIELDS, S., JORDT, S.-E., BASBAUM, A. I., CHAO, M. V. & JULIUS, D. (2001). Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957-962 | [Medline] |
| DAVIS, J. B., GRAY, J., GUNTHORPE, M. J., HATCHER, J. P., DAVEY, P. T., OVEREND, P., HARRIES, M. H., LATCHAM, J., CLAPHAM, C., ATKINSON, K., HUGHES, S. A., RANCE, K., GRAU, E., HARPER, A. J., PUGH, P. L., ROGERS, D. C., BINGHAM, S., RANDALL, A. & SHEARDOWN, S. A. (2000). Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183-187 | [Medline] |
| GARCÉS, A., HAASE, G., AIRAKSINEN, M. S., LIVET, J., FILIPPI, P. & DELAPEYRIÉRE, O. (2000). GFR1 is required for development of distinct subpopulations of motorneuron. Journal of Neuroscience 20, 4992-5000 |
[Abstract/Full Text] |
| GERKE, M. B. & PLENDERLEITH, M. B. (2001). Binding sites for the plant lectin Bandeiraea simplicifolia I-isolectin B4 are expressed by nociceptive primary sensory neurons. Brain Research 911, 101-104 | [Medline] |
| GÜLER, A. D., LEE, H., IIDA, T., SHIMIZU, I., TOMINAGA, M. & CATERINA, M. (2002). Heat-evoked activation of the ion channel, TRPV4. Journal of Neuroscience 22, 6408-6414 | [Abstract/Full Text] |
| HEPPENSTALL, P. A. & LEWIN G. R. (2000). Neurotrophins, nociceptors and pain. Current Opinion in Anaesthesiology 13, 573-576 | |
| HEUCKEROTH, R. O., ENOMOTO, H., GRIDER, J. R., GOLDEN, J. P., HANKE, J. A., JACKMAN, A., MOLLIVER, D. C., BARDGETT, M. E., SNIDER, W. D., JOHNSON, E. M. JR & MILBRANDT, J. (1999). Gene targeting reveals a critical role for neurturin in the development and maintenance of enteric, sensory, and parasympathetic neurons. Neuron 22, 253-263 | [Medline] |
| KOLTZENBURG, M., STUCKY, C. L. & LEWIN, G. R. (1997). Receptive properties of mouse sensory neurons innervating hairy skin. Journal of Neurophysiology 78, 1841-1850 | [Abstract/Full Text] |
| KRESS, M., KOLTZENBURG, M., REEH, P. W. & HANDWERKER, H. O. (1992). Responsiveness and functional attributes of electrically localized terminals of cutaneous C-fibers in vivo and in vitro. Journal of Neurophysiology 68, 581-595 | [Abstract] |
| MOLLIVER, D. C., WRIGHT, D. E., LEITNER, M. L., PARSADANIAN, A. S., DOSTER, K., WEN, D., YAN, Q. & SNIDER, W. D. (1997). IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19, 849-861 | [Medline] |
| PEIER, A. M., REEVE, A. J., ANDERSSON, D. A., MOQRICH, A., EARLEY, T. J., HERGARDEN, A. C., STORY, G. M., COLLEY, S., HOGENESCH, J. B., MCINTYRE, P., BEVAN S. & PATAPOUTIAN, A. (2002). A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046-2049 | |
| PESQUERO, J. B., ARAUJO, R. C., HEPPENSTALL, P. A., STUCKY, C. L., SILVA, J. A. JR, WALTHER, T., OLIVEIRA, S. M., PESQUERO, J. L., PAIVA, A. C., CALIXTO, J. B., LEWIN, G. R. & BADER, M. (2000). Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proceedings of the National Academy of Sciences of the USA 97, 8140-8145 | [Abstract/Full Text] |
| ROSSI, J., LUUKKO, K., POTERYAEV, D., LAURIKAINEN, A., SUN, Y. F., LAAKSO, T., EERIKAINEN, S., TUOMINEN, R., LAKSO, M., RAUVALA, H., ARUMAE, U., PASTERNACK, M., SAARMA, M. & AIRAKSINEN, M. S. (1999). Retarded growth and deficits in the enteric and parasympathetic nervous system in mice lacking GFR alpha2, a functional neurturin receptor. Neuron 22, 243-252 | [Medline] |
| SHU, X. & MENDELL, L. (1999). Nerve growth factor acutely sensitizes the response of adult rat sensory neurons to capsaicin. Neuroscience Letters 274, 159-162 | [Medline] |
| SHU, X. & MENDELL, L. M. (2001). Acute sensitization by NGF of the response of small-diameter sensory neurons to capsaicin. Journal of Neurophysiology 86, 2931-2938 | [Abstract/Full Text] |
| SMITH, G. D., GUNTHORPE, M. J., KELSELL, R. E., HAYES, P. D., REILLY, P., FACER, P., WRIGHT, J. E., JERMAN, J. C., WALHIN, J. P., OOI, L., EGERTON, J., CHARLES, K. J., SMART, D., RANDALL, A. D., ANAND, P. & DAVIS, J. B. (2002). TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418, 186-190 | [Medline] |
| SNIDER, W. D. & MCMAHON, S. B. (1998). Tackling pain at the source: new ideas about nociceptors. Neuron 20, 629-632 | [Medline] |
| STUCKY, C. L., KOLTZENBURG, M., SCHNEIDER, M., ENGLE, M. G., ALBERS, K. M. & DAVIS, B. M. (1999). Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors. Journal of Neuroscience 19, 8509-8516 | [Abstract/Full Text] |
| STUCKY, C. L. & LEWIN, G. R. (1999). Isolectin B4-positive and -negative nociceptors are functionally distinct. Journal of Neuroscience 19, 6497-6505 | [Abstract/Full Text] |
| VULCHANOVA, L., OLSON, T. H., STONE, L. S., RIEDL, M. S., ELDE, R. & HONDA, C. N. (2001). Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108, 143-155 | [Medline] |
| ZWICK, M., DAVIS, B. M., WOODBURY, C. J., BURKETT, J. N., KOERBER, H. R., SIMPSON, J. F. & ALBERS, K. M. (2002). Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. Journal of Neuroscience 22, 4057-4065 | [Abstract/Full Text] |
Acknowledgements
This work was supported by a DFG grant SP 1026 to G.R.L., an Academy of Finland grant to M.S.A. and a NIH grant NS40538 to C.L.S. The technical assistance of Emily McGinley and Anke Kanehl is gratefully acknowledged.
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