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Changes in skin levels of two neutotrophins (glial cell line derived neurotrohicfactor and neurotrophin-3) cause alterations in cutaneous neuron responses tomechanical stimuli

Jeffrey Lawson, Sabrina L. McIlwrath, H. Richard Koerber

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

摘要

Neurotrophins are important for the development and maintenance of both high and low threshold mechanoreceptors(HTMRs and LTMRs). In this series of studies, the effects of constitutive overexpression of two different neurotrophins, neurotrophin-3(NT-3) and glial cell line derived neurotrohic factor (GDNF), were examined. Previous studies indicated that both of them may beimplicated in the normal development of mouse dorsal root ganglion (DRG) neurons. Neurons from mice transgenically altered tooverexpress NT-3 or GDNF (NT-3-OE or GDNF-OE mice) in the skin were examined using several physiological, immunohistochemicaland molecular techniques. Ex vivo skin/ nerve/DRG/spinal cord and skin/ nerve preparations were used to determine the responsecharacteristics of the cutaneous neurons; immunohistochemistry was used to examine the biochemical phenotype of DRG cells and theskin; RT-PCR was used to examine the levels of candidate ion channels in skin and DRG that may correlate with changes in physiologicalresponses. In GDNF-OE mice, I-isolectin B4 (IB4)-immunopositive C-HTMRs (nociceptors), a large percentage of which aresensitive to GDNF, had significantly lower mechanical thresholds than wildtype (WT) neurons. Heat thresholds for the same cells werenot different. Mechanical sensitivity changes in GDNF-OE mice were correlated with significant increases in acid sensing ion channels2a (ASIC2a) and 2b (ASIC2b) and transient receptor potential channel A1 (TRPA1), all of which are putative mechanosensitive ionchannels. Overexpression of NT-3 affected the responses of A-LTMRs and A-HTMRs, but had no effect on C-HTMRs. Slowlyadapting type 1 (SA1) LTMRs and A-HTMRs had increased mechanical sensitivity compared to WT. Mechanical sensitivity wascorrelated with significant increases in acid-sensing ion channels ASIC1 and ASIC3. This data indicates that both neurotrophins playroles in determining mechanical thresholds of cutaneous HTMRs and LTMRs and that sensitivity changes involve the ASIC family ofputative mechanoreceptive ion channels.

关键词： dorsal root ganglion; sensory neurons; nociceptors; transgenic mice

Changes in skin levels of two neutotrophins (glial cell line derived neurotrohicfactor and neurotrophin-3) cause alterations in cutaneous neuron responses tomechanical stimuli

Jeffrey Lawson, Sabrina L. McIlwrath, H. Richard Koerber

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA

Abstract

Neurotrophins are important for the development and maintenance of both high and low threshold mechanoreceptors(HTMRs and LTMRs). In this series of studies, the effects of constitutive overexpression of two different neurotrophins, neurotrophin-3(NT-3) and glial cell line derived neurotrohic factor (GDNF), were examined. Previous studies indicated that both of them may beimplicated in the normal development of mouse dorsal root ganglion (DRG) neurons. Neurons from mice transgenically altered tooverexpress NT-3 or GDNF (NT-3-OE or GDNF-OE mice) in the skin were examined using several physiological, immunohistochemicaland molecular techniques. Ex vivo skin/ nerve/DRG/spinal cord and skin/ nerve preparations were used to determine the responsecharacteristics of the cutaneous neurons; immunohistochemistry was used to examine the biochemical phenotype of DRG cells and theskin; RT-PCR was used to examine the levels of candidate ion channels in skin and DRG that may correlate with changes in physiologicalresponses. In GDNF-OE mice, I-isolectin B4 (IB4)-immunopositive C-HTMRs (nociceptors), a large percentage of which aresensitive to GDNF, had significantly lower mechanical thresholds than wildtype (WT) neurons. Heat thresholds for the same cells werenot different. Mechanical sensitivity changes in GDNF-OE mice were correlated with significant increases in acid sensing ion channels2a (ASIC2a) and 2b (ASIC2b) and transient receptor potential channel A1 (TRPA1), all of which are putative mechanosensitive ionchannels. Overexpression of NT-3 affected the responses of A-LTMRs and A-HTMRs, but had no effect on C-HTMRs. Slowlyadapting type 1 (SA1) LTMRs and A-HTMRs had increased mechanical sensitivity compared to WT. Mechanical sensitivity wascorrelated with significant increases in acid-sensing ion channels ASIC1 and ASIC3. This data indicates that both neurotrophins playroles in determining mechanical thresholds of cutaneous HTMRs and LTMRs and that sensitivity changes involve the ASIC family ofputative mechanoreceptive ion channels.

Key words: dorsal root ganglion; sensory neurons; nociceptors; transgenic mice

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引用本文：

Jeffrey Lawson, Sabrina L. McIlwrath, H. Richard Koerber. Changes in skin levels of two neutotrophins (glial cell line derived neurotrohicfactor and neurotrophin-3) cause alterations in cutaneous neuron responses tomechanical stimuli[J]. 生理学报 2008; 60 (5): 584-596.

Jeffrey Lawson, Sabrina L. McIlwrath, H. Richard Koerber. Changes in skin levels of two neutotrophins (glial cell line derived neurotrohicfactor and neurotrophin-3) cause alterations in cutaneous neuron responses tomechanical stimuli. Acta Physiol Sin 2008; 60 (5): 584-596 (in Chinese with English abstract).