In vitro receptor binding properties of a “painless” NGF mutein, linked to hereditary sensory autonomic neuropathy type V

Covaceuszach, Sonia; Capsoni, Simona; Marinelli, Sara; Pavone, Flaminia; Ceci, Marcello; Ugolini, Gabriele; Vignone, Domenico; Amato, Gianluca; Paoletti, Francesca; Lamba, Doriano; Cattaneo, Antonino

doi:10.1016/j.bbrc.2009.11.146

Cited by 51 publications

(86 citation statements)

References 33 publications

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“…The intranasal administration of NGF and oral administration of two AchE inhibitors -ganstigmine and donepezil -improve the performance of two tests related to hippocampal function (for place and context for object recognition and memory) in AD11 mouse. 81 Relevantly, the drug is in phase IIa studies in the United States for senile dementia associated with Alzheimer's disease (AD). 82 One of the main problem related to NGF administration in vivo is the large dimension of this molecule that does not easily cross the blood-brain barrier, and on the short half-life.…”

Section: Ngf As a Potential Therapeutic Agent For Ad: In Vivo Validationmentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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Section: Ngf As a Potential Therapeutic Agent For Ad: In Vivo Validationmentioning

confidence: 99%

Does the term ‘trophic’ actually mean anti-amyloidogenic? The case of NGF

et al. 2010

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“…In vitro proNGF shows a lower binding affinity to TrkA than NGF (supplementary material Fig. S2) (Paoletti et al, 2009;Covaceuszach et al, 2010); consistently, in vivo proNGF induces lower receptor phosphorylation levels than NGF (Fahnestock et al, 2004). We find that proNGF induces a lower number of TrkA receptor trajectories populating regions 5 and 2 (Fig.…”

Section: Discussionmentioning

confidence: 52%

“…Equimolar doses of NGF, NGF R100E and proNGF were used, and NT-3 was administered in a 10-fold molar excess over NGF, as reported (Harrington et al, 2011;Kuruvilla et al, 2004). Recombinant proNGF and NGF R100E mutant were expressed in E. coli and purified as described (Covaceuszach et al, 2010). All ligands were added as two-times concentrated, pre-warmed (37˚C) solutions to an equal volume of imaging medium directly into Willco-dishH glass-bottomed chambers used for microscopy.…”

Section: Ligand Treatmentsmentioning

confidence: 99%

Ligand signature in the membrane dynamics of single TrkA receptor molecules

Marchetti

Callegari

Luin

et al. 2013

Journal of Cell Science

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SummaryThe neurotrophin receptor TrkA (also known as NTRK1) is known to be crucially involved in several physio-pathological processes. However, a clear description of the early steps of ligand-induced TrkA responses at the cell plasma membrane is missing. We have exploited single particle tracking and TIRF microscopy to study TrkA membrane lateral mobility and changes of oligomerization state upon binding of diverse TrkA agonists (NGF, NGF R100E HSANV mutant, proNGF and NT-3). We show that, in the absence of ligands, most of the TrkA receptors are fast moving monomers characterized by an average diffusion coefficient of 0.47 mm 2 /second; about 20% of TrkA molecules move at least an order of magnitude slower and around 4% are almost immobile within regions of about 0.6 mm diameter. Ligand binding results in increased slow and/or immobile populations over the fast one, slowing down of non-immobile trajectories and reduction of confinement areas, observations that are consistent with the formation of receptor dimeric and oligomeric states. We demonstrate that the extent of TrkA lateral mobility modification is strictly ligand dependent and that each ligand promotes distinct trajectory patterns of TrkA receptors at the cell membrane (ligand 'fingerprinting' effect). This ligand signature of receptor dynamics results from a differential combination of receptor-binding affinity, intracellular effectors recruited in the signalling platforms and formation of signalling and/or recycling endosome precursors. Thus, our data uncover a close correlation between the initial receptor membrane dynamics triggered upon binding and the specific biological outcomes induced by different ligands for the same receptor.

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“…Mutations in the TrkA gene seem to contribute to the condition of congenital insensitivity to pain with anhydrosis (CIPA), which in addition to producing an inability to feel pain is associated with renal failure and mental retardation [ 49 ]. However, the rarer condition of congenital insensitivity to pain without anhydrosis has only a loss of deep pain perception with other sensory modalities left intact and is the result of a NGF abnormality that prevents its normal binding to the p75 NTR receptor while the TrkA binding is unaffected [ 51 ]. Since pain treatment cannot be targeted during human development, the role of NGF in the adult becomes more relevant.…”

Section: Anti-nerve Growth Factor Antibodiesmentioning

confidence: 98%