Chapter 16
CNS Cell Signaling
Ramendra Saha, Keshore Bidasee, and Kalipada Pahan
1.
Neurotrophins are employed for regulation and/or maintenance of axonal growth, dentritic pruning and
synaptic refinements. List receptors for neurotrophins and mechanisms by which neurotrophin-receptor
complexes become internalized.
2.
Three Trk receptor tyrosine kinases and four neurotrophins have been identified in the brain. How is
affinity and specificity of neurotropins for Trk receptors regulated?
3.
Ca2+ regulates a wide array of neuronal functions. How can this single ion regulate such a diverse
functions as neuronal functions, ranging from neurite outgrowth, synaptic plasticity, transmitter release,
etc?
4.
Ca2+ is mobilized from two pools for elevating intracellular levels: the extracellular space and from
intracellular endoplasmic reticulum (ER). Give examples ion channels on the plasma and the ER
membranes that are used for mobilizing Ca2+.
5.
After conveying a signal, intracellular Ca2+ levels must be restored to resting (basal) levels intracellular
levels: Give examples of proteins (pump) on plasma and ER membranes that are used to lower
intracellular Ca2+ levels.
6.
Which of the following signaling pathways is expected to antagonize the activation of mitogen-activated
protein (MAP) kinase in brain cells?
a. JNK signaling
b. cGMP signaling
c. cAMP signaling
d. Akt signaling
e. JAK signaling
7.
Which of the following signaling pathways will be upregulated in microglia after stimulation with
interferon-g (IFN-γ)?
a. cAMP-PKA pathway
b. cGMP-PKG pathway
c. JAK-STAT pathway
d. PI-3 kinase-Akt pathway
e. TLR4 pathway
8.
Multiple sclerosis (MS) is the most common human demyelinating disorder of the CNS. The expression of
some genes may increase in the CNS of patients with MS. Identify those genes.
a. MOG
b. MBP
c. MAG
d. Nogo
e. PLP
9.
Alzheimer’s disease (AD) is the most common neurodegenerative disease in which a particular set of
neurons undergoes apoptotic cell death. Identify a signaling path-way that may attenuate neuronal
apoptosis in patients with AD.
a. JNK signaling
b. p38 MAP kinase signaling
c. bcl2 signaling
d. Rho kinase signaling
e. Ceramide signaling
16.
CNS Cell Signaling
Ramendra Saha, Keshore Bidasee, and Kalipada Pahan
2
10. In normal human brain, cells are equipped to counteract inflammatory signaling transduced by
proinflammatory cytokines. Which one of the following molecules is expected to counteract such
inflammatory signaling?
a. Ras signaling
b. Rac signaling
c. SOCS signaling
d. Nitric oxide signaling
e. Rho kinase signaling
11. One of the following molecules should play an active role in transcriptional upregulation of memory
genes in the CNS. Identify that molecule.
a. CREB
b. bad
c. bax
d. HDAC
e. Lingo
12. During glial activation, microglia release superoxide that may lead to oxidative stress in the CNS. Which
one of the following enzymes should be actively involved in pro-ducing superoxide radicals during
microglial activation?
a. NADPH oxidase
b. SOD
c. Catalase
d. Acyl-CoA oxidase
e. Glucose oxidase
13. What is nuclear factor-κB (NF-κB)? Describe the status of NF-κB in normal brain cells. What are the
possible signaling mechanisms for the activation of NF-κB? How is the activation of NF-κB related to
neuroinflammatory diseases like MS and meningitis?
14. What is a mitogen? How do the mitogens generally signal for the abnormal cell growth? How can you
possibly inhibit mitogen-induced abnormal cell growth?
15. Is mitogen-induced signaling involved in the pathogenesis of brain cancer? If yes, then explain with
possible reasons and therapeutic targets.
16.
CNS Cell Signaling
Ramendra Saha, Keshore Bidasee, and Kalipada Pahan
3
Answers
1. Neurotrophins are employed for regulation and/or maintenance of axonal growth, dentritic pruning and
synaptic refinements. List receptors for neurotrophins and mechanisms by which neurotrophin-receptor
complexes become internalized.
Trk receptor tyrosine kinases and p75 neurotrophin receptor are the receptors for neurotrophins
Receptors for neurotrophins are TrK A, TrkB and TrkC. The neurotrophin-Trk receptor complex is internalized
by four mechanistically diverse and highly regulated pathways: (i) macropinocytosis; (ii) clathrin-mediated
endocytosis; (iii) caveolae-mediated endocytosis; (iv)Pincher-mediated endocytosis. The kinase activity of Trk
is probably required for receptor internalization.
2.
Three Trk receptor tyrosine kinases and four neurotrophins have been identified in the brain. How is
affinity and specificity of neurotropins for Trk receptors regulated?
Binding of neurotrophins is the primary mechanism by which Trk receptors are activated but the affinity and
specificity of neurotrophins for Trk receptors is regulated by p75NTR. For example, the association of p75NTR
with Trk receptors induces a conformation that has high affinity for NGF. Association of p75NTR also enhances
the discrimination of Trk for their preferred neurotrophin ligand.
3.
Ca2+ regulates a wide array of neuronal functions. How can this single ion regulate such a diverse
functions as neuronal functions, ranging from neurite outgrowth, synaptic plasticity, transmitter release,
etc?
Ca2+ can regulate such diverse functions as neuronal functions, ranging from neurite outgrowth, synaptic
plasticity, transmitter release, etc by virtue of the quantity of release (amplitude), where in the neuron it is
release (spatial location) and for how long it was release (time).
4.
Ca2+ is mobilized from two pools for elevating intracellular levels: the extracellular space and from
intracellular endoplasmic reticulum (ER). Give examples ion channels on the plasma and the ER
membranes that are used for mobilizing Ca2+.
Ca2+ can be mobilized from external stores (extracellular space) following activation of ligand-gated channel
(e.g., NMDA and P2X receptors), voltage-operated Ca2+ channels (L-type, T-type and N-type Ca2+ channels) or
from internal stores (endoplasmic reticulum) via activation of inositol 1,4,5-trisphosphate receptors (InsP3R)
and ryanodine receptors (RyR).
5.
After conveying a signal, intracellular Ca2+ levels must be restored to resting (basal) levels intracellular
levels: Give examples of proteins (pump) on plasma and ER membranes that are used to lower
intracellular Ca2+ levels.
After the physiological task is completed, the influxed Ca2+ is removed from the cytoplasm by plasma
membrane bound Ca2+-ATPases (PMCA) and Na+-Ca2+ exchangers. Ca2+ that are mobilized from the
endoplasmic reticulum are returned to the stores via sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA).
6.
c
7.
e
8.
c and d
9.
c
10. c
11. a
12. a