Electrical Activity Suppresses Axon Growth through Cav1.2 Channels in Adult Primary Sensory Neurons

Enes, Joana; Langwieser, Nicolas; Ruschel, Jörg; Carballosa-Gonzalez, Melissa M.; Klug, Achim; Traut, Matthias H.; Ylera, Bhavna; Tahirović, Sabina; Hofmann, Franz; Stein, Valentin; Moosmang, Sven; Hentall, Ian D.; Bradke, Frank

doi:10.1016/j.cub.2010.05.055

Cited by 90 publications

(102 citation statements)

References 53 publications

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“…Cav1.2 is widely expressed in the heart, pancreas, adrenal gland, and nervous system (Snutch et al, 1991;Dirksen and Beam, 1996). It has been shown that Cav1.2 is located both pre-and postsynaptically in the brain (Tippens et al, 2008) and is present on peripheral nerve axons (Enes et al, 2010). Data from 4-AP-treated samples were first normalized by using the loading (GAPDH) control and then normalized to the control group (without 4-AP).…”

Section: Discussionmentioning

confidence: 99%

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Chen

et al. 2014

Mol Pharmacol

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4-Aminopyridine (4-AP, fampridine) is used clinically to improve neuromuscular function in patients with multiple sclerosis, spinal cord injury, and myasthenia gravis. 4-AP can increase neuromuscular and synaptic transmission by directly stimulating high voltageactivated (HVA) Ca 21 channels independent of its blocking effect on voltage-activated K 1 channels. Here we provide new evidence that the potentiating effect of 4-AP on HVA Ca 21 channels depends on the specific combination of voltage-activated calcium channel a1 (Cava 1 ) and voltage-activated calcium channel b (Cavb) subunits. Among the four Cavb subunits examined, Cavb3 was the most significant subunit involved in the 4-AP-induced potentiation of both L-type and N-type currents. Of particular note, 4-AP at micromolar concentrations selectively potentiated L-type currents reconstituted with Cav1.2, a 2 d1, and Cavb3. In contrast, 4-AP potentiated N-type currents only at much higher concentrations and had little effect on P/Q-type currents. In a phrenic nerve-diaphragm preparation, blocking L-type Ca 21 channels eliminated the potentiating effect of low concentrations of 4-AP on end-plate potentials. Furthermore, 4-AP enhanced the physical interaction of Cav1.2 and Cav2.2 subunits to Cavb3 and also increased their trafficking to the plasma membrane. Site-directed mutagenesis identified specific regions in the guanylate kinase, HOOK, and C-terminus domains of the Cavb3 subunit crucial to the ability of 4-AP to potentiate L-type and N-type currents. Our findings indicate that 4-AP potentiates HVA Ca 21 channels by enhancing reciprocal Cav1.2-Cavb3 and Cav2.2-Cavb3 interactions. The therapeutic effect of 4-AP on neuromuscular function is probably mediated by its actions on Cavb3-containing L-type Ca 21 channels.

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Section: Discussionmentioning

confidence: 99%

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Chen

et al. 2014

Mol Pharmacol

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“…Studies have demonstrated that this condition causes structural, electrophysiological, molecular and metabolic changes in mammalian dorsal root ganglia (DRG) cells and spinal cord. These changes include progressive loss of cells (Oliveira, 2001;Jiang and Jakobsen, 2010), proliferation and activation of satellite glial cells (Hanani, 2005) and reorganisation of the metabolic priorities of neural cells (Enes et al, 2010). There is evidence that the transection of facial and hypoglossal nerves produces a significant increase in glucose utilisation in motor nuclei of these nerves in rats (Kreutzberg and Emmert, 1980).…”

Section: Introductionmentioning

confidence: 99%

Effects of sciatic nerve transection on glucose uptake in the presence and absence of lactate in the frog dorsal root ganglia and spinal cord

et al. 2014

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Frogs have been used as an alternative model to study pain mechanisms because the simplicity of their nervous tissue and the phylogenetic aspect of this question. One of these models is the sciatic nerve transection (SNT), which mimics the clinical symptoms of "phantom limb", a condition that arises in humans after amputation or transverse spinal lesions. In mammals, the SNT increases glucose metabolism in the central nervous system, and the lactate generated appears to serve as an energy source for nerve cells. An answerable question is whether there is elevated glucose uptake in the dorsal root ganglia (DRG) after peripheral axotomy. As glucose is the major energy substrate for frog nervous tissue, and these animals accumulate lactic acid under some conditions, bullfrogs Lithobates catesbeianus were used to demonstrate the effect of SNT on DRG and spinal cord 1-[ C-2-DG uptake was lower when lactate was added to the incubation medium. No change was found in glucose and lactate oxidation after SNT, but lactate and glucose levels in the blood were reduced. Thus, our results showed that SNT increased the glucose metabolism in the frog DRG and spinal cord. The effect of lactate on this uptake suggests that glucose is used in glycolytic pathways after SNT. Efeito da secção do nervo isquiático sobre a captação de glicose na presença e ausência de lactato em gânglio da raiz dorsal e medula espinhal de rãs ResumoAs rãs são usadas como modelos experimentais alternativos no estudo da nocicepção, tanto pela simplicidade do seu tecido nervoso como por permitirem uma abordagem filogenética sobre o tema. Um desses modelos é a secção do nervo isquiático (SNI), o qual simula os sintomas clínicos do "membro fantasma", uma condição que ocorre nos humanos após amputação ou secção completa da medula espinal. Em mamíferos, a SNI aumenta o metabolismo da glicose no sistema nervoso central, e o lactato é uma fonte energética para as células nervosas. Porém é desconhecido se essa é a situação em gânglio da raiz dorsal (GRD). Como a glicose é o principal substrato energético para o tecido nervoso de rãs, e a concentração plasmática de lactato está aumentada nesses animais em distintas situações, a rã-touro Lithobates catesbeianus foi usada para demonstrar os efeitos da SNI sobre a captação de 1-[ 14 C] 2-deoxi-D-glicose ( 14 C-2-DG), na presença e ausência de lactato, em GRD e medula espinal. Foram demonstrados ainda os efeitos dessa condição experimental sobre a formação de 14 CO 2 a partir de 14 C-glicose e 14 C-L-lactato, e a concentração plasmática de glicose e lactato. A captação de 3-O-[14 C] metil-D-glicose ( 14 C-3-OMG) foi usada para demonstrar a relação tecido/meio estável da glicose nessas condições. A captação de 14 C-2-DG aumentou três dias após a SNI, sem qualquer alteração na captação de 14 C-3-OMG. O aumento foi reduzido quando o lactato foi acrescentado ao meio de incubação. A taxa de oxidação da glicose e do lactato não modificou após SNI, mas houve redução na concentração plasmática de glicose e lactato. Ass...

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“…The L-VGCC and, specifically, its pore-forming subunit Ca v 1.2 are important components in neuronal calcium signaling and play a central role in lesion conditioning (5). We performed experiments to further define the channel's role in DLK-independent regeneration and ectopic outgrowth.…”

Section: Reduction Of Sensory and Calcium Activity And Elevation Of Cmentioning

confidence: 99%

“…A striking exception to this paradigm is lesion conditioning, a phenomenon exemplified by the dorsal root ganglion (DRG), where peripheral axon damage enables robust central axon regeneration (4). The peripheral lesion is thought to revert the neuron to a growth-permissive state in an activity-dependent manner (5). These observations suggest that activity-dependent inhibitors of neurite outgrowth may represent a potent therapeutic target for enhancing neuronal regeneration in the face of injury or disease.…”

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confidence: 99%

Novel DLK-independent neuronal regeneration in Caenorhabditis elegans shares links with activity-dependent ectopic outgrowth

Chung

Awal

Shay

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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During development, a neuron transitions from a state of rapid growth to a stable morphology, and neurons within the adult mammalian CNS lose their ability to effectively regenerate in response to injury. Here, we identify a novel form of neuronal regeneration, which is remarkably independent of DLK-1/DLK, KGB-1/JNK, and other MAPK signaling factors known to mediate regeneration in Caenorhabditis elegans, Drosophila, and mammals. This DLK-independent regeneration in C. elegans has direct genetic and molecular links to a well-studied form of endogenous activity-dependent ectopic axon outgrowth in the same neuron type. Both neuron outgrowth types are triggered by physical lesion of the sensory dendrite or mutations disrupting sensory activity, calcium signaling, or genes that restrict outgrowth during neuronal maturation, such as SAX-1/NDR kinase or UNC-43/CaMKII. These connections suggest that ectopic outgrowth represents a powerful platform for gene discovery in neuronal regeneration. Moreover, we note numerous similarities between C. elegans DLK-independent regeneration and lesion conditioning, a phenomenon producing robust regeneration in the mammalian CNS. Both regeneration types are triggered by lesion of a sensory neurite via reduction of neuronal activity and enhanced by disrupting L-type calcium channels or elevating cAMP. Taken as a whole, our study unites disparate forms of neuronal outgrowth to uncover fresh molecular insights into activity-dependent control of the adult nervous system's intrinsic regenerative capacity.lesion conditioning | axon regeneration | femtosecond laser ablation | DLK-1 | activity-dependent ectopic axon outgrowth O ne of the principal goals of modern neuroscience is the comprehensive understanding and therapeutic application of neuronal regeneration (1). This goal is particularly relevant in the case of the mammalian central nervous system (CNS), which regenerates poorly. Efforts to enhance axon regeneration generally fall into two broad categories: eliminating or blocking nonpermissive extrinsic inhibitors or promoting a neuron's intrinsic regenerative capacity (2). Although much research in previous decades focused on the extrinsic angle, recent encouraging developments, particularly in invertebrate models, increasingly examine the cell intrinsic control of regeneration. Studies demonstrate that axon regeneration recruits or recapitulates mechanisms involved in a diverse range of biological processes, including synapse formation, stress response, apoptosis, and development.During development, neuronal electrical activity acts as a common intracellular feedback mechanism to establish appropriate connections and modulate outgrowth (3). Subsequently, a neuron transitions from a state of rapid growth to a stable morphology, and neurons within the adult mammalian CNS lose their ability to effectively regenerate in response to injury. A striking exception to this paradigm is lesion conditioning, a phenomenon exemplified by the dorsal root ganglion (DRG), where peripheral axon damag...

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Electrical Activity Suppresses Axon Growth through Cav1.2 Channels in Adult Primary Sensory Neurons

Abstract: Our data indicate that cessation of electrical activity after peripheral lesion contributes to the regenerative response observed upon conditioning and might be necessary to promote regeneration after central nervous system injury.

Cited by 90 publications

References 53 publications

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Effects of sciatic nerve transection on glucose uptake in the presence and absence of lactate in the frog dorsal root ganglia and spinal cord

Novel DLK-independent neuronal regeneration in Caenorhabditis elegans shares links with activity-dependent ectopic outgrowth

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