Neuroprotection by Neurotrophic Factors and Membrane Depolarization Is Regulated by Calmodulin Kinase IV

Pérez-García, M. Jose; Gou-Fàbregas, Myriam; Pablo, Yolanda de; Llovera, Marta; Comella, Joan X.; Soler, Rosa M.

doi:10.1074/jbc.m705477200

Cited by 12 publications

(11 citation statements)

References 45 publications

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“…) and chicken motor neurons in the absence of trophic support(Perez‐Garcia et al . ), while dominant negative CaMKIV blocks the survival promoting effects of 30 mM KCl. It should be noted that CaMKIV regulates a number of downstream transcription and signalling targets, which most recently includes phosphorylation of salt‐induced kinase (SIK2), a negative regulator of CREB activity in neurons (Sasaki et al .…”

Section: Discussionmentioning

confidence: 99%

Calmodulin Kinase IV–dependent CREB activation is required for neuroprotection via NMDA receptor‐PSD95 disruption

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Meese-Tamuri

et al. 2013

Journal of Neurochemistry

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NMDA-type glutamate receptors mediate both trophic and excitotoxic signalling in CNS neurons. We have previously shown that blocking NMDAR-post-synaptic density-95 (PSD95) interactions provides significant protection from excitotoxicity and in vivo ischaemia; however, the mechanism of neuroprotection is unclear. Here, we report that blocking PSD-95 interactions with the Tat-NR2B9c peptide enhances a Ca 2 + -dependent protective pathway converging on cAMPResponse Element binding protein (CREB) activation. We provide evidence that Tat-NR2B9c neuroprotection from oxygen glucose deprivation and NMDA toxicity occurs in parallel with the activation of calmodulin kinase signalling and is dependent on a sustained phosphorylation of the CREB transcription factor and its activator CaMKIV. Tat-NR2B9c-dependent neuroprotection and CREB phosphorylation are blocked by coapplication of CaM kinase (KN93 and STO-609) or CREB (KG-501) inhibitors, and by siRNA knockdown of CaMKIV. These results are mirrored in vivo in a rat model of permanent focal ischaemia. Tat-NR2B9c application significantly reduces infarct size and causes a selective and sustained elevation in CaMKIV phosphorylation; effects which are blocked by coadministration of KN93. Thus, calcium-dependent nuclear signalling via CaMKIV and CREB is critical for neuroprotection via NMDAR-PSD95 blockade, both in vitro and in vivo. This study highlights the importance of maintaining neuronal function following ischaemic injury. Future stroke research should target neurotrophic and pro-survival signal pathways in the development of novel neuroprotective strategies.

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Section: Discussionmentioning

confidence: 99%

Calmodulin Kinase IV–dependent CREB activation is required for neuroprotection via NMDA receptor‐PSD95 disruption

Bell

Bent

Meese-Tamuri

et al. 2013

Journal of Neurochemistry

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“…Dysregulation of [Ca 2+ ] i homeostasis has been implicated in cell death in a large number of neural conditions including neurotrophin withdrawal (Franklin and Johnson, 1992; De Bernardi et al, 1996; Soler et al, 1998; Perez-Garcia et al, 2004; Perez-Garcia et al, 2008), excitotoxicity (Bading et al, 1993; Lerea and McNamara, 1993; Sattler et al, 1998; Szydlowska and Tymianski, 2010), and afferent deprivation during development (Zirpel et al, 1995; Zirpel and Rubel, 1996; Zirpel et al, 1998). The occurrence of a short, high intensity peak of [Ca 2+ ] cyt in dying hair cells is also observed in neurons shortly following mitochondrial potential collapse (Nicholls et al, 1999; Nicholls and Budd, 2000).…”

Section: Discussionmentioning

confidence: 99%

Disruption of Intracellular Calcium Regulation Is Integral to Aminoglycoside-Induced Hair Cell Death

et al. 2013

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Intracellular Ca2+ is a key regulator of life or death decisions in cultured neurons and sensory cells. The role of Ca2+ in these processes is less clear in vivo, as the location of these cells often impedes visualization of intracellular Ca2+ dynamics. We generated transgenic zebrafish lines that express the genetically encoded Ca2+ indicator GCaMP in mechanosensory hair cells of the lateral line. These lines allow us to monitor intracellular Ca2+ dynamics in real time during aminoglycoside-induced hair cell death. Following exposure of live larvae to aminoglycosides, dying hair cells undergo a transient increase in intracellular Ca2+ that occurs shortly after mitochondrial membrane potential collapse. Inhibition of intracellular Ca2+ elevation through either caged chelators or pharmacological inhibitors of Ca2+ effectors mitigates toxic effects of aminoglycoside exposure. Conversely, artificial elevation of intracellular Ca2+ by caged Ca2+ release agents sensitizes hair cells to the toxic effects of aminoglycosides. These data suggest that alterations in intracellular Ca2+ homeostasis play an essential role in aminoglycoside-induced hair cell death, and indicate several potential therapeutic targets to stem ototoxicity.

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“…64,65 Therefore, our acute stimulation must counteract some of these early checks on neuron viability and axon growth, which is consistent with in vitro data that show that depolarization improves survival of motoneurons. 44,66 One hour of electrical stimulation may change cytoplasmic Ca 2 + through release of intracellular Ca 2 + stores, Ca 2 + influx, and/or movement of Ca 2 + into the nucleus. 67 Elevated Ca 2 + can trigger activation of cAMPresponse element-dependent gene expression (CREB) and at least 30 min of electrical stimulation is needed to reach maximal levels of CREB phosphorylation, an upstream regulator of brain-derived neurotrophic factor gene transcription.…”

Section: Electrical Stimulation Increased Motoneuron Survival and Axomentioning

confidence: 99%

Acute Stimulation of Transplanted Neurons Improves Motoneuron Survival, Axon Growth, and Muscle Reinnervation

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Liu

Thomas

et al. 2013

Journal of Neurotrauma

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Few options exist for treatment of pervasive motoneuron death after spinal cord injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis. Local transplantation of embryonic motoneurons into an axotomized peripheral nerve is a promising approach to arrest the atrophy of denervated muscles; however, muscle reinnervation is limited by poor motoneuron survival. The aim of the present study was to test whether acute electrical stimulation of transplanted embryonic neurons promotes motoneuron survival, axon growth, and muscle reinnervation. The sciatic nerve of adult Fischer rats was transected to mimic the widespread denervation seen after disease or injury. Acutely dissociated rat embryonic ventral spinal cord cells were transplanted into the distal tibial nerve stump as a neuron source for muscle reinnervation. Immediately post-transplantation, the cells were stimulated at 20 Hz for 1 h. Other groups were used to control for the cell transplantation and stimulation. When neurons were stimulated acutely, there were significantly more neurons, including cholinergic neurons, 10 weeks after transplantation. This led to enhanced numbers of myelinated axons, reinnervation of more muscle fibers, and more medial and lateral gastrocnemius muscles were functionally connected to the transplant. Reinnervation reduced muscle atrophy significantly. These data support the concept that electrical stimulation rescues transplanted motoneurons and facilitates muscle reinnervation.

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Neuroprotection by Neurotrophic Factors and Membrane Depolarization Is Regulated by Calmodulin Kinase IV

Cited by 12 publications

References 45 publications

Calmodulin Kinase IV–dependent CREB activation is required for neuroprotection via NMDA receptor‐PSD95 disruption

Calmodulin Kinase IV–dependent CREB activation is required for neuroprotection via NMDA receptor‐PSD95 disruption

Disruption of Intracellular Calcium Regulation Is Integral to Aminoglycoside-Induced Hair Cell Death

Acute Stimulation of Transplanted Neurons Improves Motoneuron Survival, Axon Growth, and Muscle Reinnervation

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