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Vol. 54, Issue 2, 233-246, June 2002
Pharmaceutical Sciences Institute, Aston University,
Birmingham, United Kingdom (D.R.P.); Howard Florey Institute of
Experimental Physiology and Medicine, University of Melbourne,
Victoria, Australia (P.M.S.); Department of Pharmacology, University
College London, London, United Kingdom (I.M.); AstraZeneca
Pharmaceuticals, Alderley Edge, Cheshire, United Kingdom (D.M.S.);
Douglas Hospital Research Centre and Department of Psychiatry, McGill
University, Verdun, Quebec, Canada (R.Q.); Research Laboratory for
Calcium Metabolism, Departments of Orthopedic Surgery and Medicine,
University of Zurich, Klinik Balgrist, Zurich, Switzerland (W.A.B.,
R.M., J.A.F.); and GlaxoSmithKline, Medicines Research Centre,
Stevenage, Hertfordshire, United Kingdom (S.M.F.)
I. Introduction
II. The Calcitonin Gene-Related Peptide Receptors
A. Additional Cofactors or Receptors
B. Tissue Factors
C. Contribution of More than One Receptor to pA2 Values
III. The Adrenomedullin Receptors
IV. The Calcitonin Receptors
V. The Amylin Receptors
VI. Receptor Modulation
A. Expression of mRNA Encoding Calcitonin-Like Receptor, Calcitonin
Receptor, and Receptor Activity Modifying Proteins
VII. Receptor Effector Mechanisms
VIII. The Evolution of Receptor Activity Modifying Proteins, The
Calcitonin Peptide Family, and Its Receptors
IX. Conclusions and Recommendations
References
The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors.
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