title: Immunohistochemical localization of calcitonin receptor-like receptor and receptor activity-modifying proteins in the human cerebral vasculature.
abstract: Calcitonin gene-related peptide and adrenomedullin belong to a structurally related neuropeptide family and are potent vasodilators expressed in the trigeminovascular system. The molecular identity of receptors for these proteins has only recently been elucidated. Central to functional binding of these neuropeptides is the G-protein-coupled receptor, the calcitonin receptor-like receptor (CRLR), whose cell surface expression and pharmacology is determined by coexpression of a receptor activity-modifying protein (RAMP). CRLR combined with RAMP binds calcitonin gene-related peptide with high affinity, whereas CRLR coexpression with RAMP2 or -3 confers high-affinity binding of adrenomedullin. The authors investigated the expression of these receptor components in human cerebral vasculature to further characterize neuropeptide receptor content and the potential functions of these receptors. Localization has been carried out using specific antisera raised against immunogenic peptide sequences that were subsequently applied using modern immunohistochemical techniques and confocal microscopy. The results are the first to show the presence of these receptor component proteins in human middle meningeal, middle cerebral, pial, and superficial temporal vessels, and confirm that both calcitonin gene-related peptide and adrenomedullin receptors may arise from the coassembly of RAMPs with CRLR in these vessel types. These novel data advance the understanding of the molecular function of the trigeminovascular system, its potential role in vascular headache disorders such as migraine, and may lead to possible ways in which future synthetic ligands may be applied to manage these disorders.
authors.affiliation: The Neuroscience Research Center, Merck, Sharp and Dohme Research Laboratories, Terling's Park, Harlow, Essex CM20 2QR, United Kingdom. kevin_oliver@merck.com
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Oliver
authors.forename: Anna
authors.initials: A
authors.lastname: Wainwright
authors.forename: Lars
authors.initials: L
authors.lastname: Edvinsson
authors.forename: John D
authors.initials: JD
authors.lastname: Pickard
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Hill
mesh_terms: D001345:Autoradiography; D001808:Blood Vessels / Q000737:chemistry*; D001921:Brain / Q000098:blood supply*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D058286:Calcitonin Receptor-Like Protein; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000737:chemistry; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008565:Membrane Proteins / Q000032:analysis*; D018613:Microscopy, Confocal; D012333:RNA, Messenger / Q000032:analysis; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000032:analysis* / Q000235:genetics; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000032:analysis / Q000378:metabolism
chemical_list: C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D008565:Membrane Proteins; C545503:RAMP2 protein, human; D012333:RNA, Messenger; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D018015:Receptors, Calcitonin Gene-Related Peptide; D015740:Calcitonin Gene-Related Peptide