Activation of protein kinase CβI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons

Abstract

neuroprotective effects of PKC activators were suppressed by pre-treatment with LY294002 (a PI3K inhibitor) and with U0126 (a MEK inhibitor), indicating that PKC activators promote the survival and neurite outgrowth of SGNs by both PI3K/Akt and MEK/ERK-dependent mechanisms. In addition, whereas combining the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was shown to provide only an additive effect on SGN survival, the interaction between PKC and neurotrophin signalling gave rise to a synergistic increase in SGN survival. Taken together, the data indicate that PKC␤ ␤I activation represents a key factor for the protection of the integrity of neural elements in the cochlea. (Zirrgiebel et al., 1995). Moreover, PKC inhibitors induce apoptosis in cortical (Koh et al., 1995) and cerebellar granule neurons (Zirrgiebel et al., 1995), as well as in neuronal cell lines (Behrens et al., 1999;Zhang et al., 1995). However, PKC activation does not attenuate apoptosis of rat sympathetic ganglion neurons induced by serum or nerve growth factor (NGF) deprivation (Creedon et al., 1996;Martin et al., 1992).One of the most ubiquitous families of growth factors involved in SGN survival is the neurotrophin family, which signals through the Trk family of receptor tyrosine kinases. Binding of neurotrophins to their respective Trk receptors can virtually activate at least three major signalling pathways in neurons: the mitogen-activated protein kinase kinase/ extracellular signal-regulated protein kinase (MEK/ERK), phosphoinositide 3-kinase (PI3K)/Akt and phospholipase C␥1 (PLC␥1) pathways (Huang and Reichardt, 2003;Kaplan and Miller, 2000), whose the relative functional contribution can differ according to the neuronal cell type. In the cochlea, conventional PKCs (cPKCs) have also been hypothesised to be involved in synaptic repair of auditory neuron dendrites after overstimulation of glutamate receptors, an in vivo model of sudden deafness after acoustic trauma or ischemia (LernerNatoli et al., 1997). In the experiments presented here, we investigated the role of PKC activation in SGN survival and neuritogenesis. We found that the PKC␤I isoform is exclusively expressed in neural elements of the cochlea and that PKC activators, such as phorbol esters and bryostatin 1, a new safe anti-cancer agent (Clamp and Jayson, 2002), rescue SGNs from cell death and enhance neuritic outgrowth in vitro via the activation of PKC␤I.On studying the intracellular pathways involved in these trophic actions, we showed that PI3K and MEK/ERK are required for the survival-promoting effect of both neurotrophins and PKC activators, whereas PKC␤I is only involved in PKC-activator-induced neuroprotection. Moreover, when assuming the additive effect on SGN survival using PKC activators and neurotrophins, of particular relevance was the first demonstration that these two extrinsic cues actually synergise to regulate neuronal survival in the cochlea. Materials and Methods ChemicalsPoly-L-ornithine, DNAse, U0126, LY294002, 4␤-phorb...

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

“…For example, PKC activators can reverse some of the neurological damage in an ischemia/hypoxia model for stroke (5). PKC activators are also reported to induce expression of tyrosine hydroxylase (39) and induce neuronal survival and neurite outgrowth (8,40). These neurotrophic effects may be mediated by neurotrophins such as brain-derived neurotrophic factor (40,41).…”

“…PKC activators are also reported to induce expression of tyrosine hydroxylase (39) and induce neuronal survival and neurite outgrowth (8,40). These neurotrophic effects may be mediated by neurotrophins such as brain-derived neurotrophic factor (40,41). Neurotrophin signaling and APP metabolism pathways intersect at many points.…”

Increased Sensitivity to Noise-Induced Hearing Loss by Blockade of Endogenous PI3K/Akt Signaling

“…A decrease in p-Akt (S473) in sensory hair cells is also involved in age-related hearing impairment (Sha et al 2010). On the other hand, Akt has been implicated as an integral part of the protein kinase C (PKC) pathway that promotes spiral ganglion neuron survival (Lallemend et al 2005). In rat cochlear explants, treatment with an Akt inhibitor promotes gentamicininduced outer hair cell (OHC) death (Chung et al 2006) and diminishes the protective function of dexamethasone against TNFα-initiated apoptosis (Haake et al 2009).…”

Interplay Between Protein Kinase C Isoforms Alpha and Epsilon, Neurofibromin, and the Ras/MAPK Pathway in Neuroblastoma Differentiation

“…Nonetheless, these data attest to a developmental time-dependent function of neurofibromin during neuronal differentiation. Many studies in neuronal cell lines and primary neurons have implicated most of PKC isoforms in survival and differentiation mechanisms Hundle et al, 1997;Lallemend et al, 2005;Shirai et al, 2008). In their majority, PKCs have been shown to have a positive role in neuritic outgrowth; yet, in a recent large-scale analysis in hippocampal neurons PKC and PKC scored as potent negative neurite growth regulators (Buchser et al, 2010).…”