Localization of CGRP Receptor Components, CGRP, and Receptor Binding Sites in Human and Rhesus Cerebellar Cortex
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The cerebellum is classically considered to be mainly involved in motor processing, but studies have suggested several other functions, including pain processing. Calcitonin-gene-related peptide (CGRP) is a neuropeptide involved in migraine pathology, where there is elevated release of CGRP during migraine attacks and CGRP receptor antagonists have antimigraine efficacy. In the present study, we examined CGRP and CGRP receptor binding sites and protein expression in primate cerebellar cortex. Additionally, mRNA expression of the CGRP receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), was examined. In addition, expression of procalcitonin was studied. We observed high [3H]MK-3207 (CGRP receptor antagonist) binding densities in the molecular layer of rhesus cerebellar cortex; however, due to the limit of resolution of the autoradiographic image the exact cellular localization could not be determined. Similarly, [125I]CGRP binding was observed in the molecular layer and Purkinje cell layer of human cerebellum. CLR and RAMP1 mRNA was expressed within the Purkinje cell layer and some expression was found in the molecular layer. Immunofluorescence revealed expression of CGRP, CLR, and RAMP1 in the Purkinje cells and in cells in the molecular layer. Procalcitonin was found in the same localization. Recent research in the biology of cerebellum indicates that it may have a role in nociception. For the first time we have identified CGRP and CGRP receptor binding sites together with CGRP receptor expression through protein and mRNA localization in primate cerebellar cortex. These results point toward a functional role of CGRP in cerebellum. Further efforts are needed to evaluate this.
KeywordsCerebellum Nociception CGRP CLR RAMP1 Primate
Thanks are due to the following from Merck Research Laboratories: Stephanie Villarreal and John Majercak for their consultation on design and methodology details. Kenneth Lodge for collecting the rhesus tissue, Brett Connolly for H&E staining, and Patricia Miller for tissue preparation. Dr. Elisabet Englund at Lund University, Sweden, and Dr. Janos Tajiti at Albert Szent-Györgyi University Medical School, Szeged, Hungary, for providing the human tissue.
Conflict of Interest
The authors do not have any conflicts of interest related to this work.
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