Rees Tayla A, Russo Andrew F, O'Carroll Simon J, Hay Debbie L, Walker Christopher S
School of Biological Sciences, University of Auckland, Auckland, New Zealand.
Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Front Physiol. 2022 May 10;13:860037. doi: 10.3389/fphys.2022.860037. eCollection 2022.
The neuropeptide calcitonin gene-related peptide (CGRP) is expressed in the trigeminal ganglia, a key site in craniofacial pain and migraine. CGRP potently activates two receptors: the CGRP receptor and the AMY receptor. These receptors are heterodimers consisting of receptor activity-modifying protein 1 (RAMP1) with either the calcitonin receptor-like receptor (CLR) to form the CGRP receptor or the calcitonin receptor (CTR) to form the AMY receptor. The expression of the CGRP receptor in trigeminal ganglia has been described in several studies; however, there is comparatively limited data available describing AMY receptor expression and in which cellular subtypes it is found. This research aimed to determine the relative distributions of the AMY receptor subunit, CTR, and CGRP in neurons or glia in rat, mouse and human trigeminal ganglia. Antibodies against CTR, CGRP and neuronal/glial cell markers were applied to trigeminal ganglia sections to investigate their distribution. CTR-like and CGRP-like immunoreactivity were observed in both discrete and overlapping populations of neurons. In rats and mice, 30-40% of trigeminal ganglia neurons displayed CTR-like immunoreactivity in their cell bodies, with approximately 78-80% of these also containing CGRP-like immunoreactivity. Although human cases were more variable, a similar overall pattern of CTR-like immunoreactivity to rodents was observed in the human trigeminal ganglia. CTR and CGRP appeared to be primarily colocalized in small to medium sized neurons, suggesting that colocalization of CTR and CGRP may occur in C-fiber neurons. CGRP-like or CTR-like immunoreactivity were not typically observed in glial cells. Western blotting confirmed that CTR was expressed in the trigeminal ganglia of all three species. These results confirm that CTR is expressed in trigeminal ganglia neurons. The identification of populations of neurons that express both CGRP and CTR suggests that CGRP could act in an autocrine manner through a CTR-based receptor, such as the AMY receptor. Overall, this suggests that a trigeminal ganglia CTR-based receptor may be activated during migraine and could therefore represent a potential target to develop treatments for craniofacial pain and migraine.
神经肽降钙素基因相关肽（CGRP）在三叉神经节中表达，三叉神经节是颅面疼痛和偏头痛的关键部位。CGRP能有效激活两种受体：CGRP受体和AMY受体。这些受体是异二聚体，由受体活性修饰蛋白1（RAMP1）与降钙素受体样受体（CLR）组成CGRP受体或与降钙素受体（CTR）组成AMY受体。多项研究描述了CGRP受体在三叉神经节中的表达；然而，关于AMY受体表达及其在哪些细胞亚型中存在的数据相对有限。本研究旨在确定AMY受体亚基CTR和CGRP在大鼠、小鼠和人类三叉神经节神经元或神经胶质细胞中的相对分布。将针对CTR、CGRP和神经元/神经胶质细胞标志物的抗体应用于三叉神经节切片，以研究它们的分布。在离散和重叠的神经元群体中均观察到CTR样和CGRP样免疫反应性。在大鼠和小鼠中，30 - 40%的三叉神经节神经元在其细胞体中显示出CTR样免疫反应性，其中约78 - 80%也含有CGRP样免疫反应性。虽然人类病例的变异性更大，但在人类三叉神经节中观察到与啮齿动物相似的总体CTR样免疫反应性模式。CTR和CGRP似乎主要共定位于中小尺寸神经元，这表明CTR和CGRP的共定位可能发生在C纤维神经元中。在神经胶质细胞中通常未观察到CGRP样或CTR样免疫反应性。蛋白质印迹法证实CTR在所有三个物种的三叉神经节中均有表达。这些结果证实CTR在三叉神经节神经元中表达。同时表达CGRP和CTR的神经元群体的鉴定表明，CGRP可能通过基于CTR的受体（如AMY受体）以自分泌方式发挥作用。总体而言，这表明基于三叉神经节CTR的受体可能在偏头痛期间被激活，因此可能是开发颅面疼痛和偏头痛治疗方法的潜在靶点。
