NEUS 609 - Neurotrophins

Neurotrophins

family of proteins with crucial functions in all cells of the nervous system

nerve growth factor

NGF

brain derived neurotrophin factor

BDNF

neurotrophin 3

NT3

neurotrophin 4/5

NT4/5

Rita Levi Montalcini

NGF was isolated in 1952 by ___ and got her the Nobel prize of chmistry and medicine in 1986 shafred with Stanley Cohen

neurite

any part of a neural cell body that protrude, be it either axon or dendrites

outgrowth, survival

NGF promotes neurites ___ & neuronal ___

tyrosine kinase receptors

neurotrophins bind to ___ aka Trks

• they have an extracellular ligand binding domain

• they have an intracellular kinase domain that phosphorylate tyrosine residues in other proteins

neurotrophins binding process

1. ligand binding induces receptor subunits dimerization

2. dimerization results in autophosphorylation in kinase domains fully activating kinase activity

3. phosphorylation of other tyrosine residues creates specific binding sites for other proteins

TrkA

NGF binds to __ receptor

TrkB

BDNF and NT4/5 bind to ___ receptor

TrkC, TrkB

NT3 binds to ___ receptor with low affinity for __ receptor

p75

ALL neurotrophins have low binding affinity for the __ receptor

high affinity

• Trk receptors

• strong interactions

• need low ligand concentration to function

low affinity

• p75 receptor

• weak interactions

• need high ligand concentration to function

oppose

the p75 activated pathways tend to ___ the actions of Trk activated pathways

pro-neurotrophins

precursor moelcules for neurotrophins

ALL

__ pro-neurotrophins bind to p75 receptor

• which pro-neurotrophins and neurotrophins bind is based on context and concentrations

proteins activated by p75 pathways

• SC1: schwann cell factor 1

• NADE: NTR-associated cell death executor

• RhoA: member of GTPase family

furin, protein convertase

pro-neurotrophins can be cleaved intracellularly by ___ or ___

plasmin, metalloproteinase

pro-neurotrophins can be cleaved extracellularly by ___ or ___

neural plasticity

balance between pro-neurotrophins and neurotrophins play a role in ___

other proteins p75 associate with

• lingo 1

• sortilin

• trk (differentiation and survival)

lingo1

p75 assoociated protein inhibiting axonal growth

sortilin

p75 associated protein dealing with apoptyosis and CNS plasticity

neurotrophins control

• stem cell development

• glial differentiation

• memory and learning

• regeneration

• neuronal differentiation

function, specificity

neurotrophins ___ and ___ are determined by:

• cell and receptor types

• associated signaling cascades

• receptor subcellular location

myelinating proteins

in myelinating oligodendrocytes, NT3 stimulates ___ expression by activating the initiation of their mRNA translation

Retrograde axon signaling

1. neurotrophins bind to Trk receptors at the neural terminal

2. local activation of PI3 kinase pathway which promote axonal growth and receptor endocytosis

3. activated receptors within terminal and axon activate Erk1/2 pathway promoting axon growth

4. dyenin transport signaling endosomes retrogradely along axon microtubules

5. signlaing endosomes activates 2 cell body pathways both promoting survival: PI3 kinase (ATK kinase prevent sapoptosis) & Erk5 (CREB support survival)

BDNF

pre-synaptic membrane secrete ___ which increases the number of receptors on post-synaptic membrane

post-synaptic membrane secrete ___ which enhance neurotrnasmitter release by pre-synaptic membrane

adaptive stress response

good diet, regular exercise, and cognitive stimulation lead to an ____ which trigger the production of BDNF and helps with neurogenesis, neuroprotection, and synaptic plasticity

social interactions

even ___ can alter neurotrophin signaling

• isolated rats had more anxiety behavior and decreased Tkr and BDNF signaling leading to behavioral impairments

epigenetically

BDNF signaling is ___ regulated in anxiety and affective diseases via microRNAs