90 SECTION IIPhysiology of Nerve & Muscle Cells
RECEPTORS
Four established neurotrophins and their three high-affinity
receptors are listed in Table 4–4. Each of these trk receptors
dimerizes, and this initiates autophosphorylation in the cyto-
plasmic tyrosine kinase domains of the receptors. An addi-
tional low-affinity NGF receptor that is a 75-kDa protein is
called p75NTR. This receptor binds all four of the listed neu-
rotrophins with equal affinity. There is some evidence that it
can form a heterodimer with trk A monomer and that the
dimer has increased affinity and specificity for NGF. However,
it now appears that p75NTR receptors can form homodimers
that in the absence of trk receptors cause apoptosis, an effect
opposite to the usual growth-promoting and nurturing effects
of neurotrophins.
ACTIONS
The first neurotrophin to be characterized was NGF, a protein
growth factor that is necessary for the growth and maintenance
of sympathetic neurons and some sensory neurons. It is present
in a broad spectrum of animal species, including humans, and
is found in many different tissues. In male mice, there is a par-
ticularly high concentration in the submandibular salivary
glands, and the level is reduced by castration to that seen in fe-
males. The factor is made up of two α, two β, and two γ sub-
units. The β subunits, each of which has a molecular mass of
13,200 Da, have all the nerve growth-promoting activity, the α
subunits have trypsinlike activity, and the γ subunits are serine
proteases. The function of the proteases is unknown. The struc-
ture of the β unit of NGF resembles that of insulin.
NGF is picked up by neurons and is transported in retro-
grade fashion from the endings of the neurons to their cell
bodies. It is also present in the brain and appears to be
responsible for the growth and maintenance of cholinergic
neurons in the basal forebrain and striatum. Injection of anti-
serum against NGF in newborn animals leads to near total
destruction of the sympathetic ganglia; it thus produces an
immunosympathectomy. There is evidence that the mainte-
nance of neurons by NGF is due to a reduction in apoptosis.
Brain-derived neurotrophic factor (BDNF), neurotrophin 3
(NT-3), NT-4/5, and NGF each maintain a different pattern of
neurons, although there is some overlap. Disruption of NT-3
by gene knockout causes a marked loss of cutaneous mechan-
oreceptors, even in heterozygotes. BDNF acts rapidly and canTABLE 4–3 Relative susceptibility of
mammalian A, B, and C nerve fibers to
conduction block produced by various agents.
Susceptibility to:Most
Susceptible IntermediateLeast
Susceptible
Hypoxia B A C
Pressure A B C
Local anesthetics C B ATABLE 4–4 Neurotrophins.
Neurotrophin Receptor
Nerve growth factor (NGF) trk A
Brain-derived neurotrophic factor (BDNF) trk B
Neurotrophin 3 (NT-3) trk C, less on trk A and trk B
Neurotrophin 4/5 (NT-4/5) trk BCLINICAL BOX 4–2
Axonal Regeneration
Peripheral nerve damage is often reversible. Although the
axon will degenerate distal to the damage, connective ele-
ments of the so-called distal stump often survive. Axonal
sprouting occurs from the proximal stump, growing to-
ward the nerve ending. This results from growth-promot-
ing factors secreted by Schwann cells that attract axons
toward the distal stump. Adhesion molecules of the immu-
noglobulin superfamily (eg, NgCAM/L1) promote axon
growth along cell membranes and extracellular matrices.
Inhibitory molecules in the perineurium assure that the re-
generating axons grow in a correct trajectory. Denervated
distal stumps are able to upregulate production of neu-
rotrophins that promote growth. Once the regenerated
axon reaches its target, a new functional connection (eg,
neuromuscular junction) is formed. Regeneration allows for
considerable, although not full, recovery. For example, fine
motor control may be permanently impaired because
some motor neurons are guided to an inappropriate motor
fiber. Nonetheless, recovery of peripheral nerves from dam-
age far surpasses that of central nerve pathways. The proxi-
mal stump of a damaged axon in the CNS will form short
sprouts, but distant stump recovery is rare, and the dam-
aged axons are unlikely to form new synapses. This is be-
cause CNS neurons do not have the growth-promoting
chemicals needed for regeneration. In fact, CNS myelin is a
potent inhibitor of axonal growth. In addition, following
CNS injury several events—astrocytic proliferation, acti-
vation of microglia, scar formation, inflammation, and
invasion of immune cells—provide an inappropriate envi-
ronment for regeneration. Thus, treatment of brain and spi-
nal cord injuries frequently focuses on rehabilitation rather
than reversing the nerve damage. New research is aiming
to identify ways to initiate and maintain axonal growth, to
direct regenerating axons to reconnect with their target
neurons, and to reconstitute original neuronal circuitry.