Localization of the CGRP family of peptides in relation to the
TGV system.
CGRP is expressed in a granular pattern in small
(<30 µm) to medium (30-60 µm) sized TG neurons (Eftekhari,
Salvatore, Calamari, Kane, Tajti & Edvinsson, 2010; Lennerz et al.,
2008) where CGRP is packed in vesicles that are surrounded by the Golgi
apparatus. In addition, C-type of sensory unmyelinated nerves appear as
pearl-like CGRP immunoreactivity (ir) in boutons (also known as
varicosities) (Figure 1). The myelinated fibres do not contain CGRP as
sometimes has been proposed (Eftekhari, Warfvinge, Blixt & Edvinsson,
2013; Lennerz et al., 2008). The CGRP receptor components, CLR and
RAMP1, are co-expressed in medium to large (>60 µm)
diameter neurons (Eftekhari et al., 2016; Eftekhari, Salvatore,
Calamari, Kane, Tajti & Edvinsson, 2010). In addition, CLR and RAMP1
have been observed in satellite glial cells (SGC) and in thinly
myelinated fibres, typical for Aδ-fibres in various parts of the TGV
system such as the TG, dura mater, and root entry zone (Figure 1)
(Eftekhari, Salvatore, Calamari, Kane, Tajti & Edvinsson, 2010; Lennerz
et al., 2008; Miller et al., 2016). Early findings, which have today
been confirmed by many researchers, has stood the test of time, and
served a solid base for the successful development of mAbs and small
molecule gepants (Edvinsson, Haanes, Warfvinge & Krause, 2018).
CT is a hormone produced mainly by C cells in the
thyroid gland with a role to reduce plasma calcium and to promote bone
formation (Findlay & Sexton, 2004). In the clinic, CT is used in
treatment of bone disorders characterized by increased bone resorption,
osteoporosis and hypercalcemia due to malignancy, with some pain relief
(Findlay & Sexton, 2004). Thus, CT and its receptor CTR are seen in
different cell types and tissues which suggests multiple physiological
roles, including bone metabolism (Findlay & Sexton, 2004). CT has not
been shown to be expressed in the nervous system, however binding sites
for CT are found in many brain structures (Hendrikse, Bower, Hay &
Walker, 2018). In addition, a recent study has revealed the presence of
the CT receptor in the human brainstem (Bower et al., 2016).
Recently, CT was found to be expressed in the trigeminal system; CT the
peptide was found in vesicles that are surrounded by the endoplasmic
reticulum/Golgi apparatus and occur in addition as pearl-like
CT-immunoreactivity (ir) in the C-type of sensory fibres (Figure 1B)
(Edvinsson, Grell & Warfvinge, 2020).
. The CT-ir was expressed in a pattern like that of CGRP; granular
staining of small to medium sized neurons and pearl-like staining of
fibres in the TG. In addition, many SGCs were CT positive (Edvinsson,
Grell & Warfvinge, 2020). In a subpopulation of TG neurons there is
granular and cytosolic expression of CT-ir (Figure 1).
AMY is currently in focus of much migraine research, due
to its affinity for the CGRP receptor that pharmacologically is almost
equal to that of CGRP and because CGRP has strong affinity for the
AMY1 receptor (Hendrikse, Bower, Hay & Walker, 2018).
Comparing the binding affinity of olcegepant and
CGRP8-37 to the AMY1 and CGRP receptors
revealed similarities in binding characteristics as well as in cAMP
production (Walker et al., 2015). Human AMY was first isolated in 1987
(Cooper, Willis, Clark, Turner, Sim & Reid, 1987). It is an endocrine
hormone that signals to the brain and acts as a satiety factor; its
presence in plasma is about 10 times higher than that of CGRP (Hay,
2017). Research on AMY deposition in brain neurons has been discussed
for a role in Alzheimer’s disease (Mietlicki-Baase et al., 2017) and AMY
has been found to alter viability of human brain pericytes (Schultz,
Byman, Fex & Wennstrom, 2017).
Previously, we reported that AMY is expressed in feline TG neurons, and
that AMY relax in vitro and in vivo cerebral vessels
(Edvinsson, Goadsby & Uddman, 2001). A detailed report showed AMY
expression in a few small to medium sized TG neurons which co-express
CGRP and in C-fibres (Edvinsson, Grell & Warfvinge, 2020).
Receptors for CGRP and AMY are related and share components, CLR/RAMP1
and CTR/RAMP1, respectively. Given the close relationship between AMY
and CGRP, and since release of the peptides may act on either or both
receptors, it is understandable that experiments with AMY aimed to
trigger migraine and to block migraine with mAbs towards AMY are on the
way. However, early result from a trial on migraine patients did not
reveal any prophylactic effect of the mAbs towards AMY (Ashina, 2019).
AM is most often considered an endothelial peptide and
was first isolated in 1993 (Kitamura et al., 1993). AM is generally
expressed and participates in a variety of physiological functions
including vasodilation, bronchodilatation, growth and hormone regulation
(Ferrero et al., 2018). Furthermore, AM is involved in
pathophysiological processes such as hypertension, retinopathy and
tumour genesis (Ferrero, Larrayoz, Gil-Bea, Martinez & Ramirez, 2018).
In mammals, endothelial AM-ir is present in low concentrations in the
vascular endothelium (Satoh et al., 1996). AM is found in neurons and
glial cells (Serrano et al., 2000). We have reported the presence of
AM-ir in the thin cytoplasm of the glial cells, SGCs and cells
enveloping neuronal processes, probably myelinating cells. In addition,
AM-ir has been noted to occur in cranial vascular endothelium
(Edvinsson, Grell & Warfvinge, 2020). Its molecular relation to CGRP
has resulted in suggestion that AM may have a role in migraine
pathophysiology (Juhl, Petersen, Larsen, Jansen-Olesen & Olesen, 2006).
However, intravenous AM infusion did not cause migraine-like attacks in
man (Ashina, Hansen, BO & Olesen, 2017). This view is in line with our
demonstration that there is no AM in TG neurons but presence in glial
cells and vascular endothelium (Edvinsson, Grell & Warfvinge, 2020).