Regulation &
Control
How
neurotrophins are regulated in the body:
Regulation of neurotrophin mRNA was first
discovered in part of the mesial temporal lobe memory system called the
hippocampus.† Epileptiform activity in
the hippocampus regulates nerve growth factor (NGF) and brain derived nerve
factor (BDNF) mRNA levels.† The mRNA
levels are induced by depolarization of cultured hippocampal neurons by high
potassium or by glutame receptor activity [2].†
The survival and growth of neurons are regulated by target-derived
neurotrophic factors.†
How
neurotrophins control neuronal cells:
†††††† Neurotrophins
can determine the outcome of the neuron surface receptor that it binds to.† The neurotrophin receptors are located on
the surface of the nerve cells.†
Neurotrophins will bind to one or more of a family of tyrosine receptor
kinases.† All neurotrophic factors can
bind to p75 neurotrophin receptor (p75NTR)The binding of the
neurotrophin to the receptor induces dimerization at the cell surface.† These phophorylated tyrosines recruit
intracellular protiens involved in tranduction[1].††
Neurotrophic factors and their receptors:†††
†††††††††††
Neurotrophins binding to Trk receptors triggers multiple
signal transduction pathways that are known to have strong posttraslational
regulatory effects on neuronal signaling proteins.† The effects of neurotrophins binding to either TrkA or p75NTR
have opposite outcomes.† NGF signals
through TrkA to promote neuronal survival, on the same neuron, BDNF signals
through p75NTR to promote neuronal apoptosis, cell death [3].†† NGF is essential for the survival of the
neuron.† Without NGF, a neuron will die
within 48 hours, however, this apoptosis is reversible.† If NGF is given back to the neurons within
15-18 hours, the cell will survive.† The
point at which the apoptotic cascade becomes permanent is called the commitment
point[3].† Neurotophin-3 (NT-3) and Neurotophin-4
(NT-4) also play a part in the survival of the neuron, but they are less
effective than NGF.† It appears that
neuron survival during the period of naturally-occuring cell death is
determined by the relative levels of activation of TrkA versus p75NTR[3].
Nerve Growth Factor/TrkA Complex
Trk binding residue
p75 Neurotrophin Receptor
How neurotrophins may effect lives in the future:
††††††††††††† The
ability of Neurotrophins to promote the survival of peripheral and central
neurons during development and after neuronal damage has stimulated the
interest in these molecules as possible therapeutic agents [4].† It is hoped that neurotrophic factorsí
effect on neuron survival and growth will be used in the treatment of
neurological diseases, including, Alzheimerís, Parkinsonís, and Amyotrophic
Lateral Sclerosis (Lou Gerhigís disease).†
††††† ††††††††††††††††††††††††††††††††††††††††††††††††††
††††††††††††††††††††††††††††††††††††††††††††††††††††††††††
[STRUCTURE] [FUNCTION] [REGULATION AND CONTROL]
References
1. http://www.rndsystems.com/search/mfs/02/cyt_catngr.html
2.
Neurotrophic
factors and Synaptic Placticity.†
Anon.† USA† Neuron (1995),† 15(5), 979-81. CODEN:NERNET ISSN: 0896-6273.† Journal; General review.
3.
http://www.promega.com/nnotes/nn303/303_03.htm
4.
Ibanez, Carlos F.† (1996), Structure, regulation and function
of neurotrophic growth factors and their receptors, pp. 1-2.
††††††
Pictures:
http://www.cryst.bbk.ac.uk/~ubcg09j/neurotrophins/nt_gallery/index.html