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Neurofibromatosis: The role of guanosine triphosphatase activating proteins in sensory neuron function

Cynthia M. Hingtgen^*

Departments of Neurology and Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA

摘要

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease characterized by formation of multiple benign andmalignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibromin, the protein productof the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21Ras (Ras). Loss of Nf1 results in an increase in activityof the Ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the Rastransduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides,substance P (SP) and calcitonin gene-related peptide (CGRP), from primary sensory neurons of mice with a mutation of the Nf1 gene(Nf1+/–). Measuring the levels of SP and CGRP by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptidesis 3-5 folds higher in spinal cord slices from Nf1+/– mice than that from wildtype mouse tissue. In addition, the potassium- andcapsaicin-stimulated release of CGRP from the culture of sensory neurons isolated from Nf1+/– mice was more than double that from theculture of wildtype neurons. Using patch-clamp electrophysiological techniques, we also examined the excitability of capsaicinsensitivesensory neurons. It was found that the number of action potentials generated by the neurons from Nf1+/– mice, responsing toa ramp of depolarizing current, was more than three times of that generated by wildtype neurons. Consistent with that observation,neurons from Nf1+/– mice had lower firing thresholds, lower rheobase currents and shorter firing latencies compared with wildtypeneurons. These data clearly demonstrate that GAPs, such as neurofibromin, can alter the excitability of nociceptive sensory neurons.The augmented response of sensory neurons with altered Ras signaling may explain the abnormal pain sensations experienced bypeople with NF1 and suggests an important role of GAPs in the mechanism of sensory neuron sensitization.

关键词： calcitonin gene-related peptide; dorsal root ganglia; neurofibromin; nerve growth factor; nociceptors; Ras

Neurofibromatosis: The role of guanosine triphosphatase activating proteins in sensory neuron function

Cynthia M. Hingtgen^*

Departments of Neurology and Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease characterized by formation of multiple benign andmalignant tumors. People with this disorder also experience chronic pain, which can be disabling. Neurofibromin, the protein productof the Nf1 gene, is a guanosine triphosphatase activating protein (GAP) for p21Ras (Ras). Loss of Nf1 results in an increase in activityof the Ras transduction cascade. Because of the growing evidence suggesting involvement of downstream components of the Rastransduction cascade in the sensitization of nociceptive sensory neurons, we examined the stimulus-evoked release of the neuropeptides,substance P (SP) and calcitonin gene-related peptide (CGRP), from primary sensory neurons of mice with a mutation of the Nf1 gene(Nf1+/–). Measuring the levels of SP and CGRP by radioimmunoassay, we demonstrated that capsaicin-stimulated release of neuropeptidesis 3-5 folds higher in spinal cord slices from Nf1+/– mice than that from wildtype mouse tissue. In addition, the potassium- andcapsaicin-stimulated release of CGRP from the culture of sensory neurons isolated from Nf1+/– mice was more than double that from theculture of wildtype neurons. Using patch-clamp electrophysiological techniques, we also examined the excitability of capsaicinsensitivesensory neurons. It was found that the number of action potentials generated by the neurons from Nf1+/– mice, responsing toa ramp of depolarizing current, was more than three times of that generated by wildtype neurons. Consistent with that observation,neurons from Nf1+/– mice had lower firing thresholds, lower rheobase currents and shorter firing latencies compared with wildtypeneurons. These data clearly demonstrate that GAPs, such as neurofibromin, can alter the excitability of nociceptive sensory neurons.The augmented response of sensory neurons with altered Ras signaling may explain the abnormal pain sensations experienced bypeople with NF1 and suggests an important role of GAPs in the mechanism of sensory neuron sensitization.

Key words: calcitonin gene-related peptide; dorsal root ganglia; neurofibromin; nerve growth factor; nociceptors; Ras

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通讯作者：Cynthia M. Hingtgen　　E-mail: chingtge@iupui.edu

引用本文：

Cynthia M. Hingtgen. Neurofibromatosis: The role of guanosine triphosphatase activating proteins in sensory neuron function[J]. 生理学报 2008; 60 (5): 581-583.

Cynthia M. Hingtgen. Neurofibromatosis: The role of guanosine triphosphatase activating proteins in sensory neuron function. Acta Physiol Sin 2008; 60 (5): 581-583 (in Chinese with English abstract).