Calcitonin Gene Related Peptide (CGRP) and GABA-mediated Tonic Inhibition in Neuroscience

This article discusses the role of Calcitonin Gene Related Peptide (CGRP) and GABA-mediated Tonic Inhibition in Neuroscience. It explains how CGRP provides an alternative means to signal a neuron that is desensitized and how GABA-mediated tonic inhibition produced excessively can be reduced to stimulate faster recovery in patients affected by a stroke. The article also elaborates on the unconventional NMDA receptor signalling.

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The Name of the Class (Course)
Professor (Tutor)
Name of School (University)
The City and State Where It Is Placed
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Question 1
Part a
Calcitonin Gene Related Peptide (CGRP) provides an alternative means to signal a
neuron that is desensitized. CGRP is a neuropeptide that has thirty-seven amino acids (Iyengar,
Ossipov, and Johnson 2017). It is produced during RNA processing of genes such as calcitonin.
CGRP occurs in two different structures, alpha CGRP or beta CGRP. It acts on unusual receptors
families that are not responsive to acetylcholine. Receptors acted on usually consist of Calcitonin
Receptor-like Receptor (CLR) that has been linked to Receptor Activity Modifying Protein
(RAMP). In patients who have had frequent exposure to acetylcholine, their receptors have a low
sensitivity to normal concentrations of acetylcholine. Very high concentrations of acetylcholine
are required to trigger the signal receptors hence CGRP is required as an alternative signalling
path to transmit signals from the presynaptic to the postsynaptic neurons (Russo 2015).
CGRP is very effective in desensitized neurons. This is because it is a highly potent
vasodilator and is localized to the C and A sensory fibres. These two fibres have wide
innervations in the body. They also have an extensive perivascular localization. Presence of
CGRP helps in sensory and efferent function. Secondly, most of the nerve terminals that release
acetylcholine also release CGRP. This means that as acetylcholine is released, CGRP is also
released. The postsynaptic neurons that have a high frequency can also receive the signal. These
two factors explain why the neurotransmitter peptide is suitable t signal postsynaptic neurons
that are desensitized (Shi et al. 2016)
Part b
Several molecular changes occur after the release of the CGRP from the neurons. These
changes are responsible for the increase in phosphorylation of nicotine receptors and the increase

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in the amount of cyclic AMP in the body. CGRP increases the amount of AMP by stimulating
the release of Sarcolemmal adenylate cyclase. Upon the release of CGRP, the AMP rise rapidly
and increase after a few miniatures and then the levels decline. The phosphorylation of the
nicotine receptors increases rapidly in response to the increase of CGRP (Lima, Marques-
Oliveira, Da Silva and Chaves 2017).
Part c
In order for these changes to occur, it is necessary that the postsynaptic neuron switches
off the receptors of the postsynaptic neurons and decrease the sensitivity to acetylcholine. A
decrease in the sensitivity of acetylcholine of the postsynaptic neurons will trigger the
presynaptic neurons to produce an alternative neuropeptide, CGRP (Aubdool, Kodji and Brain
2017).
Question 2
Part a
The primary issue addressed in the selected study explains how through reducing GABA
mediated tonic inhibition produced excessively; it is possible to stimulate faster recovery in
patients affected by a stroke. The aim of the study was to increase the neuroplasticity of the peri-
infarct zone, which will allow the sensory-motor functions to be able to redevelop from the areas
damaged by the stroke. This pharmacological therapy will help to speed up the recovery of
stroke patients (Clarkson, Huang, Mac Isaac, Mody and Carmichael 2010).
Part b
The results of the study showed that in vivo administration of benzodiazepine was
effecting in reducing heighten inhibition of tonic neuronal. Extrasynaptic GABA receptors

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mediate increased tonic inhibition. It is triggered by impairment in the GABA transporter
function. The benzodiazepine was specific for an alpha five subunit that contained the
extrasynaptic GABA receptor. The treatment initiated and enhanced the patient’s motor function
recovery by reducing the number of beta- and alpha 5- subunits that contain the GABA
receptors. These receptors play a major role in tonic inhibition (Clarkson, Huang, Mac Isaac,
Mody and Carmichael 2010).
Part c
The GABA transmission was manipulated by reducing the number of alpha 5- and beta-
subunits containing the GABA receptors. This strategy reduced the amount of tonic inhibition
that was produced by the peri-infarct zone. The experiment was conducted on mice (Clarkson,
Huang, Mac Isaac, Mody and Carmichael 2010).
Question 3
Part a
Dore, K., Stein, I.S., Brock, J.A., Castillo, P.E., Zito, K. and Sjöström, P.J., 2017.
Unconventional NMDA receptor signalling. Journal of Neuroscience, 37(45), pp.10800-10807.
Part b
According to the paper selected, NMDA is found on the postsynaptic membrane. They
are expressed to act through the calcium ions. These receptions signal the Hebbian plasticity. The
study explains that the NMDA receptor-mediated transmission can be regulated in the body
through regulating neural activity. The authors of the study elaborate that NMDA receptors are
found pre synaptically and they cannot act as detectors of conventional coincidence, but they

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have been shown to function as conventional coincidence detectors without requiring the
activation of calcium ions (Dore et al. 2017)

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References
Aubdool, A.A., Kodji, X. and Brain, S.D., 2017. Calcitonin Gene-Related Peptide (CGRP)
Clarkson, A.N., Huang, B.S., Mac Isaac, S.E., Mody, I. and Carmichael, S.T., 2010. Reducing
excessive GABA-mediated tonic inhibition promotes functional recovery after
stroke. Nature, 468(7321), p.305.
Dore, K., Stein, I.S., Brock, J.A., Castillo, P.E., Zito, K. and Sjöström, P.J., 2017.
Unconventional NMDA receptor signalling. Journal of Neuroscience, 37(45), pp.10800-10807.
Iyengar, S., Ossipov, M.H. and Johnson, K.W., 2017. The role of calcitonin gene-related peptide
in peripheral and central pain mechanisms including migraine. Pain, 158(4), p.543.
Lima, W.G., Marques-Oliveira, G.H., Da Silva, T.M. and Chaves, V.E., 2017. Role of calcitonin
gene-related peptide in energy metabolism. Endocrine, 58(1), pp.3-13.
Russo, A.F., 2015. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annual
review of pharmacology and toxicology, 55, pp.533-552.
Shi, L., Lehto, S.G., Zhu, D.X., Sun, H., Zhang, J., Smith, B.P., Immke, D.C., Wild, K.D. and
Xu, C., 2016. Pharmacologic characterization of AMG 334, a potent and selective human
monoclonal antibody against the calcitonin gene-related peptide receptor. Journal of
Pharmacology and Experimental Therapeutics, 356(1), pp.223-231.