A Ca2+/Calmodulin Kinase Inhibitor, KN-62, Inhibits Neurite Outgrowth Stimulated by CAMs and FGF

Williams, Emma J.; Mittal, Bina; Walsh, Frank S.; Doherty, Patrick

doi:10.1006/mcne.1995.1007

Cited by 81 publications

(46 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We first explored the possible involvement of CaMKII, a multifunctional kinase known to regulate several neuronal functions (for review, see Soderling et al, 2001;Lisman et al, 2002), because it had been implicated in previous studies (Zheng et al, 1994;Solem et al, 1995;Williams et al, 1995;Kuhn et al, 1998;Vaillant et al, 2002). Rather than using KN-62, which inhibits various CaMK family members, we overexpressed CaMKIIN, an endogenous protein inhibitor of CaMKII (Chang et al, 1998.…”

Section: Camkii Does Not Stimulate Axon Outgrowthmentioning

confidence: 99%

“…Many stimulatory effects of Ca 2ϩ on neurite outgrowth are blocked by the compound 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62) (Zheng et al, 1994;Solem et al, 1995;Williams et al, 1995;Kuhn et al, 1998;Vaillant et al, 2002). Because KN-62 was originally thought to be a specific calmodulin kinase II (CaMKII) inhibitor (Tokumitsu et al, 1990), it was assumed that CaMKII mediated these stimulatory Ca 2ϩ effects; however, KN-62 is now recognized to also inhibit CaMKIV and CaMKI (Mochizuki et al, 1993;Enslen et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Axonal Extension and Growth Cone Motility by Calmodulin-Dependent Protein Kinase I

Wayman¹,

Kaech²,

Grant³

et al. 2004

J. Neurosci.

173

176

View full text Add to dashboard Cite

Calcium and calmodulin (CaM) are important signaling molecules that regulate axonal or dendritic extension and branching. The Ca 2ϩ -dependent stimulation of neurite elongation has generally been assumed to be mediated by CaM-kinase II (CaMKII), although other members of the CaMK family are highly expressed in developing neurons. We have examined this assumption using a combination of dominant-negative CaMKs (dnCaMKs) and other specific CaMK inhibitors. Here we report that inhibition of cytosolic CaMKI, but not CaMKII or nuclear CaMKIV, dramatically decreases axonal outgrowth and branching in cultured neonatal hippocampal and postnatal cerebellar granule neurons. CaMKI is found throughout the cell cytosol, including the growth cone. Growth cones of neurons expressing dnCaMI or dnCaMKK, the upstream activator of CaMKI, exhibit collapsed morphology with a prominent reduction in lamellipodia. Live-cell imaging confirms that these morphological changes are associated with a dramatic decrease in growth cone motility. Treatment of neurons with 1,8-naphthoylene benzimidazole-3-carboxylic acid (STO-609), an inhibitor of CaMKK, causes a similar change in morphology and reduction in growth cone motility, and this inhibition can be rescued by transfection with an STO-609-insensitive mutant of CaMKK or by transfection with constitutively active CaMKI. These results identify CaMKI as a positive transducer of growth cone motility and axon outgrowth and provide a new physiological role for the CaMKK-CaMKI pathway.

show abstract

Section: Camkii Does Not Stimulate Axon Outgrowthmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Axonal Extension and Growth Cone Motility by Calmodulin-Dependent Protein Kinase I

Wayman¹,

Kaech²,

Grant³

et al. 2004

J. Neurosci.

173

176

View full text Add to dashboard Cite

show abstract

“…In addition, contact with LN causes a movement of organelles into the periphery of the growth cone (Rivas et al, 1992), possibly associated with the insertion of new plasma membrane. Although the molecular pathways that link receptor-substrate binding to neurite growth are not fully understood, they appear to involve calcium influx (Williams et al, 1992;Bixby et al, 1994;Kuhn et al, 1998) and activation of protein kinases and phosphatases (Bixby, 1989;Ignelzi et al, 1994;Klinz et al, 1995;Kuhn et al, 1995;Williams et al, 1995;Kunz et al, 1996). In addition to these signal-mediated events, the binding of cell surface receptors to substrate-attached ligands also may directly modify the interaction between these receptors and the submembranous actin cytoskeleton (Davis et al, 1993;Davis and Bennett, 1994;McKerracher et al, 1996), and also regulate their cell surface expression (Condic and Letourneau, 1997;Kamiguchi et al, 1998).…”

Section: Contact With a Preferred Substrate Induces A Rapid Increase mentioning

confidence: 99%

Local Presentation of Substrate Molecules Directs Axon Specification by Cultured Hippocampal Neurons

1999

View full text Add to dashboard Cite

Axon specification is a crucial, early step in neuronal development, but little is known about how this event is controlled in vivo. To test the hypothesis that local presentation of growthpromoting molecules can direct axon specification, we cultured hippocampal neurons on substrates patterned with stripes of poly-L-lysine and either laminin (LN) or the neuron-glia cell adhesion molecule (NgCAM). Although undifferentiated neurites contacted both substrates equally, axons formed preferentially on LN or NgCAM. Time-lapse studies revealed that changes in the growth pattern of a cell indicative of axon specification began almost immediately after the growth cone of one of the neurites of the cell contacted LN or NgCAM. When cells were plated on alternating stripes of LN and NgCAM, cells with their somata on LN usually formed axons on NgCAM, whereas those with somata on NgCAM preferentially formed axons on LN. This suggests that the change from one axon-promoting substrate to another also provides a signal sufficient to specify the axon. These results demonstrate that contact with preferred substrate molecules can govern which neurite becomes the axon and thus direct the development of neuronal polarity.

show abstract

“…L1 is localized primarily along the course of axons, and particularly on growth cones at points of cellular contact (6 0, 68). Calcium-independent binding of L1 molecules in adjacent membranes (homophilic binding) promotes cell-cell adhesion and activates a tyrosine kinase signaling cascade involved in neurite outgrowth (36,77,79,81). L1 also binds heterophili-…”

mentioning

confidence: 99%

Alcohol inhibits cell-cell adhesion mediated by human L1 [published erratum appears in J Cell Biol 1996 Jun;133(5):1139-40]

Ramanathan

Wilkemeyer

Mittal

et al. 1996

The Journal of Cell Biology

167

View full text Add to dashboard Cite

Abstract. Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. Ll-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited Ll-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. Ll-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit Ll-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of Ll-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of Ll-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders. FETAL alcohol syndrome (FAS) 1 is one of the most common recognizable syndromes associated with mental retardation in the Western world (1). The full syndrome, characterized by growth retardation, neurological abnormalities, and facial malformations, occurs in N5% of the offspring of alcoholic women (1, 72). Neuropathological examination and neuroimaging of children with FAS have disclosed a spectrum of neurodevelopmental abnormalities, including hydrocephalus, agenesis of the corpus callosum, neuronal-glial heterotopias, cerebellar dysplasia, and microcephaly (8,27,62). Some of these lesions arise from disordered migration of neural cells, which has also been demonstrated experimentally in animal models of FAS (45,46 X-linked syndrome associated with mutations in the gene encoding L1, an immunoglobulin cell adhesion molecule (IgCAM) (4,20,28,31,66,74,83). Three overlapping syndromes, X-linked hydrocephalus, MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and X-linked complicated spastic paraplegia, were each mapped to the same region (Xq28) of the X chromosome (32,76,82). A large number of different missense mutations, short deletions, and defects of alternative splicing within the L1 gene have been identified in individuals with these X-linked disorders (83); similar mutations have never been encountered in large numbers of control subjects. A single point mutation in L1 can cause either X-linked hydro...

show abstract

A Ca2+/Calmodulin Kinase Inhibitor, KN-62, Inhibits Neurite Outgrowth Stimulated by CAMs and FGF

Cited by 81 publications

References 0 publications

Regulation of Axonal Extension and Growth Cone Motility by Calmodulin-Dependent Protein Kinase I

Regulation of Axonal Extension and Growth Cone Motility by Calmodulin-Dependent Protein Kinase I

Local Presentation of Substrate Molecules Directs Axon Specification by Cultured Hippocampal Neurons

Alcohol inhibits cell-cell adhesion mediated by human L1 [published erratum appears in J Cell Biol 1996 Jun;133(5):1139-40]

Contact Info

Product

Resources

About