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Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.
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oral administration of pf 01247324 a subtype selective Nav1.8 blocker reverses cerebellar deficits in a mouse model of multiple sclerosis
PLOS ONE, 2015Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Shannon D Shields, Richard P ButtAbstract:Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that Sodium Channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. In the present study, we assessed the effect of per os (p.o.) dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE) model. PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders.
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Sodium Channel genes in pain related disorders phenotype genotype associations and recommendations for clinical use
Lancet Neurology, 2014Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Ingemar S J Merkies, Monique M Gerrits, Giuseppe Lauria, James J Cox, J Wood, Geoffrey C WoodsAbstract:Human studies have firmly implicated voltage-gated Sodium Channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which Sodium Channel variants are involved. Missense substitutions of SCN9A, the gene encoding Sodium Channel NaV1.7, SCN10A, the gene encoding Sodium Channel Nav1.8, and SCN11A, the gene encoding Sodium Channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in Sodium Channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.
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small fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons
The Journal of Neuroscience, 2013Co-Authors: Jianying Huang, Sulayman D Dibhajj, Ingemar S J Merkies, Monique M Gerrits, Yang Yang, Peng Zhao, Janneke G J Hoeijmakers, Kim J Bekelaar, Catharina G Faber, Stephen G WaxmanAbstract:Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated Sodium Channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium Channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional Channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant Channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
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Physiological interactions between Nav1.7 and Nav1.8 Sodium Channels: a computer simulation study
Journal of Neurophysiology, 2011Co-Authors: Jin-sung Choi, Stephen G WaxmanAbstract:We have examined the question of how the level of expression of Sodium Channel Nav1.8 affects the function of dorsal root ganglion (DRG) neurons that also express Nav1.7 Channels and, conversely, h...
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inactivation properties of Sodium Channel Nav1.8 maintain action potential amplitude in small drg neurons in the context of depolarization
Molecular Pain, 2007Co-Authors: Stephen G Waxman, Patrick T HartyAbstract:Background Small neurons of the dorsal root ganglion (DRG) express five of the nine known voltage-gated Sodium Channels. Each Channel has unique biophysical characteristics which determine how it contributes to the generation of action potentials (AP). To better understand how AP amplitude is maintained in nociceptive DRG neurons and their centrally projecting axons, which are subjected to depolarization within the dorsal horn, we investigated the dependence of AP amplitude on membrane potential, and how that dependence is altered by the presence or absence of Sodium Channel Nav1.8.
Sulayman D Dibhajj - One of the best experts on this subject based on the ideXlab platform.
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oral administration of pf 01247324 a subtype selective Nav1.8 blocker reverses cerebellar deficits in a mouse model of multiple sclerosis
PLOS ONE, 2015Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Shannon D Shields, Richard P ButtAbstract:Cerebellar symptoms significantly diminish quality of life in patients with multiple sclerosis (MS). We previously showed that Sodium Channel Nav1.8, although normally restricted to peripheral somatosensory neurons, is upregulated in the cerebellum in MS, and that Nav1.8 expression is linked to ataxia and MS-like symptoms in mice. Furthermore, intracerebroventricular administration of the Nav1.8 blocker A-803467 temporarily reversed electrophysiological and behavioral manifestations of disease in a mouse MS model; unfortunately A-803467 is not orally bioavailable, diminishing the potential for translation to human patients. In the present study, we assessed the effect of per os (p.o.) dosing of a new orally bioavailable Nav1.8-selective blocker, PF-01247324, in transgenic mice expressing Nav1.8 in Purkinje neurons, and in wildtype mice in the experimental autoimmune encephalomyelitis (EAE) model. PF-01247324 was administered by oral gavage at 1000 mg/kg; control groups received an equal volume of vehicle. Behavioral assays of motor coordination, grip strength, and ataxia were performed. We observed significant improvements in motor coordination and cerebellar-like symptoms in mice that received PF-01247324 compared to control littermates that received vehicle. These preclinical proof-of-concept data suggest that PF-01247324, its derivatives, or other Nav1.8-selective blockers merit further study for providing symptomatic therapy for cerebellar dysfunction in MS and related disorders.
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Sodium Channel genes in pain related disorders phenotype genotype associations and recommendations for clinical use
Lancet Neurology, 2014Co-Authors: Sulayman D Dibhajj, Stephen G Waxman, Ingemar S J Merkies, Monique M Gerrits, Giuseppe Lauria, James J Cox, J Wood, Geoffrey C WoodsAbstract:Human studies have firmly implicated voltage-gated Sodium Channels in human pain disorders, and targeted and massively parallel genomic sequencing is beginning to be used in clinical practice to determine which Sodium Channel variants are involved. Missense substitutions of SCN9A, the gene encoding Sodium Channel NaV1.7, SCN10A, the gene encoding Sodium Channel Nav1.8, and SCN11A, the gene encoding Sodium Channel NaV1.9, produce gain-of-function changes that contribute to pain in many human painful disorders. Genomic sequencing might help to establish a diagnosis, and in the future might support individualisation of therapeutic approaches. However, in many cases, and especially in Sodium Channelopathies, the results from genomic sequencing can only be appropriately interpreted in the context of an extensive functional assessment, or family segregation analysis of phenotype and genotype.
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small fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons
The Journal of Neuroscience, 2013Co-Authors: Jianying Huang, Sulayman D Dibhajj, Ingemar S J Merkies, Monique M Gerrits, Yang Yang, Peng Zhao, Janneke G J Hoeijmakers, Kim J Bekelaar, Catharina G Faber, Stephen G WaxmanAbstract:Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small-caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated Sodium Channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium Channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional Channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant Channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN.
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a Channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis
Annals of Neurology, 2012Co-Authors: Shannon D Shields, Xiaoyang Cheng, Andreas Gasser, Carl Y Saab, Lynda Tyrrell, Emmanuella M Eastman, Masashi Iwata, Pamela J Zwinger, Joel A Black, Sulayman D DibhajjAbstract:Objective: Cerebellar dysfunction in multiple sclerosis (MS) contributes significantly to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. We previously observed that Sodium Channel Nav1.8, whose expression is normally restricted to the peripheral nervous system, is present in cerebellar Purkinje neurons in a mouse model of MS (experimental autoimmune encephalomyelitis [EAE]) and in humans with MS. Here, we tested the hypothesis that upregulation of Nav1.8 in cerebellum in MS and EAE has functional consequences contributing to symptom burden. Methods: Electrophysiology and behavioral assessment were performed in a new transgenic mouse model overexpressing Nav1.8 in Purkinje neurons. We also measured EAE symptom progression in mice lacking Nav1.8 compared to wild-type littermates. Finally, we administered the Nav1.8-selective blocker A803467 in the context of previously established EAE to determine reversibility of MS-like deficits. Results: We report that, in the context of an otherwise healthy nervous system, ectopic expression of Nav1.8 in Purkinje neurons alters their electrophysiological properties, and disrupts coordinated motor behaviors. Additionally, we show that Nav1.8 expression contributes to symptom development in EAE. Finally, we demonstrate that abnormal patterns of Purkinje neuron firing and MS-like deficits in EAE can be partially reversed by pharmacotherapy using a Nav1.8-selective blocker. Interpretation: Our results add to the evidence that a Channelopathy contributes to cerebellar dysfunction in MS. Our data suggest that Nav1.8-specific blockers, when available for humans, merit study in MS. Ann Neurol 2012;71:186–194
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calmodulin regulates current density and frequency dependent inhibition of Sodium Channel Nav1.8 in drg neurons
Journal of Neurophysiology, 2006Co-Authors: Jin-sung Choi, Stephen G Waxman, Andy Hudmon, Sulayman D DibhajjAbstract:Sodium Channel Nav1.8 produces a slowly inactivating, tetrodotoxin-resistant current, characterized by recovery from inactivation with fast and slow components, and contributes a substantial fracti...
Yu-qiu Zhang - One of the best experts on this subject based on the ideXlab platform.
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Modulation of Nav1.8 by Lysophosphatidic Acid in the Induction of Bone Cancer Pain.
Neuroscience bulletin, 2016Co-Authors: Hai-li Pan, Ben-long Liu, Wei Lin, Yu-qiu ZhangAbstract:Given that lysophosphatidic acid (LPA) and the tetrodotoxin-resistant Sodium Channel Nav1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA1 (also known as EDG2) and Nav1.8 in the dorsal root ganglion (DRG) contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in naive rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Nav1.8 expression in L4–6 DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Nav1.8 expression in ipsilateral L4–6 DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Nav1.8 and LPA remarkably enhanced Nav1.8 currents in DRG neurons, and this was blocked by either a protein kinase C (PKC) inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Nav1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
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dexmedetomidine inhibits tetrodotoxin resistant Nav1.8 Sodium Channel activity through gi o dependent pathway in rat dorsal root ganglion neurons
Molecular Brain, 2015Co-Authors: Ben-long Liu, Hai-li Pan, Kaikai Zang, Liu Yang, Zhiqi Zhao, Yu-qiu ZhangAbstract:Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) Sodium Channel Nav1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Nav1.8 currents in acutely dissociated small-diameter DRG neurons. Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Nav1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2A-AR antagonist BRL44408 but not α2B-AR antagonist imiloxan blocked the inhibition of Nav1.8 currents by DEX. Immunohistochemistry results showed that Nav1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Nav1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or Gi/o proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Nav1.8 currents. We established a functional link between α2-AR and Nav1.8 in primary sensory neurons utilizing the Gi/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
Stephen R Ikeda - One of the best experts on this subject based on the ideXlab platform.
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a 3 7 kb fragment of the mouse scn10a gene promoter directs neural crest but not placodal lineage egfp expression in a transgenic animal
The Journal of Neuroscience, 2015Co-Authors: Stephen R Ikeda, Henry L PuhlAbstract:Under physiological conditions, the voltage-gated Sodium Channel Nav1.8 is expressed almost exclusively in primary sensory neurons. The mechanism restricting Nav1.8 expression is not entirely clear, but we have previously described a 3.7 kb fragment of the Scn10a promoter capable of recapitulating the tissue-specific expression of Nav1.8 in transfected neurons and cell lines (Puhl and Ikeda, 2008). To validate these studies in vivo, a transgenic mouse encoding EGFP under the control of this putative sensory neuron specific promoter was generated and characterized in this study. Approximately 45% of dorsal root ganglion neurons of transgenic mice were EGFP-positive (mean diameter = 26.5 μm). The majority of EGFP-positive neurons bound isolectin B4, although a small percentage (∼10%) colabeled with markers of A-fiber neurons. EGFP expression correlated well with the presence of Nav1.8 transcript (95%), Nav1.8-immunoreactivity (70%), and TTX-R INa (100%), although not all Nav1.8-expressing neurons expressed EGFP. Several cranial sensory ganglia originating from neurogenic placodes, such as the nodose ganglion, failed to express EGFP, suggesting that additional regulatory elements dictate Scn10a expression in placodal-derived sensory neurons. EGFP was also detected in discrete brain regions of transgenic mice. Quantitative PCR and Nav1.8-immunoreactivity confirmed Nav1.8 expression in the amygdala, brainstem, globus pallidus, lateral and paraventricular hypothalamus, and olfactory tubercle. TTX-R INa recorded from EGFP-positive hypothalamic neurons demonstrate the usefulness of this transgenic line to study novel roles of Nav1.8 beyond sensory neurons. Overall, Scn10a-EGFP transgenic mice recapitulate the majority of the Nav1.8 expression pattern in neural crest-derived sensory neurons.
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identification of the sensory neuron specific regulatory region for the mouse gene encoding the voltage gated Sodium Channel Nav1.8
Journal of Neurochemistry, 2008Co-Authors: Henry L Puhl, Stephen R IkedaAbstract:Voltage-gated Sodium Channels (VGSC) are critical membrane components that participate in the electrical activity of excitable cells. The type one VGSC family includes the tetrodotoxin insensitive Sodium Channel, Nav1.8, encoded by the Scn10a gene. Nav1.8 expression is restricted to small and medium diameter nociceptive sensory neurons of the dorsal root ganglia and cranial sensory ganglia. To understand the stringent transcriptional regulation of the Scn10a gene, the sensory neuron specific promoter was functionally identified. While identifying the mRNA 5′-end, alternative splicing within the 5′-UTR was observed to create heterogeneity in the RNA transcript. Four kilobases of upstream genomic DNA was cloned and the presence of tissue specific promoter activity was tested by microinjection and adenoviral infection of fluorescent protein reporter constructs into primary mouse and rat neurons, and cell lines. The region contained many putative transcription factor-binding sites and strong homology with the predicted rat ortholog. Homology to the predicted human ortholog was limited to the proximal end and several conserved cis elements were noted. Two regulatory modules were identified by microinjection of reporter constructs into dorsal root ganglia and superior cervical ganglia neurons: a neuron specific proximal promoter region between −1.6 and −0.2 kb of the transcription start site cluster, and a distal sensory neuron switch region beyond −1.6 kb that restricted fluorescent protein expression to a subset of primary sensory neurons.
Henry L Puhl - One of the best experts on this subject based on the ideXlab platform.
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a 3 7 kb fragment of the mouse scn10a gene promoter directs neural crest but not placodal lineage egfp expression in a transgenic animal
The Journal of Neuroscience, 2015Co-Authors: Stephen R Ikeda, Henry L PuhlAbstract:Under physiological conditions, the voltage-gated Sodium Channel Nav1.8 is expressed almost exclusively in primary sensory neurons. The mechanism restricting Nav1.8 expression is not entirely clear, but we have previously described a 3.7 kb fragment of the Scn10a promoter capable of recapitulating the tissue-specific expression of Nav1.8 in transfected neurons and cell lines (Puhl and Ikeda, 2008). To validate these studies in vivo, a transgenic mouse encoding EGFP under the control of this putative sensory neuron specific promoter was generated and characterized in this study. Approximately 45% of dorsal root ganglion neurons of transgenic mice were EGFP-positive (mean diameter = 26.5 μm). The majority of EGFP-positive neurons bound isolectin B4, although a small percentage (∼10%) colabeled with markers of A-fiber neurons. EGFP expression correlated well with the presence of Nav1.8 transcript (95%), Nav1.8-immunoreactivity (70%), and TTX-R INa (100%), although not all Nav1.8-expressing neurons expressed EGFP. Several cranial sensory ganglia originating from neurogenic placodes, such as the nodose ganglion, failed to express EGFP, suggesting that additional regulatory elements dictate Scn10a expression in placodal-derived sensory neurons. EGFP was also detected in discrete brain regions of transgenic mice. Quantitative PCR and Nav1.8-immunoreactivity confirmed Nav1.8 expression in the amygdala, brainstem, globus pallidus, lateral and paraventricular hypothalamus, and olfactory tubercle. TTX-R INa recorded from EGFP-positive hypothalamic neurons demonstrate the usefulness of this transgenic line to study novel roles of Nav1.8 beyond sensory neurons. Overall, Scn10a-EGFP transgenic mice recapitulate the majority of the Nav1.8 expression pattern in neural crest-derived sensory neurons.
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identification of the sensory neuron specific regulatory region for the mouse gene encoding the voltage gated Sodium Channel Nav1.8
Journal of Neurochemistry, 2008Co-Authors: Henry L Puhl, Stephen R IkedaAbstract:Voltage-gated Sodium Channels (VGSC) are critical membrane components that participate in the electrical activity of excitable cells. The type one VGSC family includes the tetrodotoxin insensitive Sodium Channel, Nav1.8, encoded by the Scn10a gene. Nav1.8 expression is restricted to small and medium diameter nociceptive sensory neurons of the dorsal root ganglia and cranial sensory ganglia. To understand the stringent transcriptional regulation of the Scn10a gene, the sensory neuron specific promoter was functionally identified. While identifying the mRNA 5′-end, alternative splicing within the 5′-UTR was observed to create heterogeneity in the RNA transcript. Four kilobases of upstream genomic DNA was cloned and the presence of tissue specific promoter activity was tested by microinjection and adenoviral infection of fluorescent protein reporter constructs into primary mouse and rat neurons, and cell lines. The region contained many putative transcription factor-binding sites and strong homology with the predicted rat ortholog. Homology to the predicted human ortholog was limited to the proximal end and several conserved cis elements were noted. Two regulatory modules were identified by microinjection of reporter constructs into dorsal root ganglia and superior cervical ganglia neurons: a neuron specific proximal promoter region between −1.6 and −0.2 kb of the transcription start site cluster, and a distal sensory neuron switch region beyond −1.6 kb that restricted fluorescent protein expression to a subset of primary sensory neurons.