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The Department of Medicine University of California, San Diego, San Diego, California 92161 and The San Diego Veterans Affairs Medical Center La Jolla, California 92161
Address all correspondence and requests for reprints to: Leonard J. Deftos, M.D., San Diego Veterans Affairs Medical Center, University of California-San Diego, 3350 La Jolla Village Drive, Room 3172, Mail Code 111C, San Diego, California 92161. E-mail: ljdeftos{at}ucsd.edu
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While these two studies continue to unravel the molecular twine of ligand-receptor interaction, neither implicated any changes in affinity nor specificity of ligand binding as molecular mechanisms. This lack of change in receptor affinity reveals something fishy about the mammalian CTR: the fact that salmon CT (SCT) and other nonmammalian CTs have a higher affinity and potency for all mammalian CT receptors, including human, than any of the native CTs that have been identified, whether homologous or heterologous to the receptor under study (1, 5, 6). This enhanced potency of SCT and the nonmammalian CTs in mammals has been repeatedly demonstrated in many clinical and biological studies, and it is the basis for the more popular use of SCT in treating humans than human CT (HCT) (4, 5, 6). In addition to the two studies in this issue of Endocrinology, many elegant studies of the CTs and the CTRs have provided important structure-function insights into the molecular enigma of SCT’s high affinity for the mammalian CTR. A brief review of the comparative studies of the CTs and CTRs and the molecular insights they provide can serve as a starting point for an inquiry into the evolutionary riddle of the high affinity of SCT for essentially all mammalian CTRs.
Over a dozen species of the CTs have been cloned and/or sequenced (5). These 32 amino acid peptides can be separated into three classes based on structural and biological similarities: teleost/avian, artiodactyl, and rat/human; the first are nonmammalian CTs of ultimobranchial (UB) gland origin, the second and third, thyroid gland CTs. All share many common features, including a 1–7 amino-terminal disulfide bridge, a conserved 4–7 sequence, a glycine at residue 28, and a carboxy-terminal proline amide residue. However, substantial divergence resides in the interior of the molecule between residues 8–27, and SCT and HCT share only 50% of their amino acids. Complex functional studies (1, 5) reveal a simple canon: basic amino acid substitutions in the interior of the CT molecule enhance potency, perhaps by conferring a helical structure to this region. Because SCT and the nonmammalian CTs are more basic and thus helical than the mammalian CTs, they consequently have the most potency, even in mammalian systems.
Comparative studies of the CTRs also provide some insights into the enhanced potency of nonmammalian CTs for mammalian CTRs (1). The CTRs are members of a subfamily of seven-transmembrane domain, G protein-coupled receptors that includes receptors for several other peptide hormones. CTRs have been cloned from the porcine, human, rat, mouse, and rabbit, but a nonmammalian CTR has yet to be cloned. CTRs are most robustly expressed in osteoclasts but are also expressed in many other sites, including the central nervous system. The mammalian CTRs share common structural and functional motifs, signal through several pathways, and can exist in several isoforms with insert sequences and/or deletions in their intracellular and extracellular domains (1, 7, 8, 9). The similar architecture of the CTR with the PTH receptor subfamily member allows reciprocal signaling of chimeras and a common pattern of ligand interaction (10). Because CTRs are monogenic, these isoforms are likely to arise from alternative splicing of receptor mRNA. Some of the isoforms of the CTR seem to have differential ligand specificity (5, 8, 9). Studies with mutations and chimeras (1, 10, 11) have suggested the following model for CT-CTR interaction: the ligand is sandwiched between the receptor’s amino-terminus and transmembrane loops, with high affinity being conferred by the helicity of the internal, nonconserved basic sequences of the CT. Signal transduction through several pathways results from the interaction of the amino-terminus of CT with the transmembrane domain of the receptor. Thus, the ligand specificity of the CTR is determined by the membrane-embedded portion of the receptors, whereas the amino-terminal, extracellular domain of the receptors affects binding affinity for the respective agonist. SCT apparently conforms best to these structural requirements for binding and signaling of mammalian CTRs, perhaps also explaining in part its sustained receptor binding and activation of cAMP (7, 8, 9). While these tentative models of the CTRs and the CTs may help to explain the molecular basis of optimal ligand-receptor interactions, they do not directly address the evolutionary enigma: why are fish CTs orders of magnitude more potent in mammals than mammalian CTs?
The recently cloned receptor for CT-gene-related-peptide (CGRP) may provide some insights about regulation of the ligand specificity of the CTR (12, 13). Luebke et al. (12) cloned a 146-amino acid protein that binds with high affinity to CGRP, the alternate mRNA splice product of the CT gene. This newly identified protein has no homology to any known receptor. It seems rather to be a CGRP binding protein that confers specificity to the recently cloned CGRP receptor (13), the newest member of the G protein-coupled receptor family. A nonreceptor ligand binding mechanism similar to CGRP’s might exist that confers receptor specificity for the CTs, which are CGRPs’ splicing siblings (12, 13).
The isoforms of the CTR may also provide some clues about its evolutionary molecular biology. An isoform that is expressed in rat brain seems to preferentially recognize SCT, and binding sites for SCT are present at several sites in the CNS (9, 10, 14). Could it be that SCT or an SCT-like ligand is produced by mammals? There is some evidence for this in both man and murine. The presence and secretion of SCT-like immunoreactive material have been described in the CNS of several mammalian species, including humans (15, 16, 17). This location is consistent with a role of a SCT-like peptide acting as a neurotransmitter, perhaps through an SCT-specific isoform of the CTR (8, 9, 18). Another fishy link between human and murine mineral metabolism may be provided by stanniocalcin; this antihypercalcemic hormone originally identified in fish has been recently identified in humans (19). Finally it is also notable that another nonmammalian CT, chicken CT, also seems more potent in humans than human CT and may be expressed in humans (1, 5, 20). Cloning of the salmon CTR as well as the chicken CTR should provide insight into molecular interactions among CTs and their receptors and may provide the answer to another Darwinian riddle: which came first for human mineral metabolism, the chicken or the roe?
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Received November 19, 1996.
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-thyrotropin thyrotroph cell line.
Endocrinology 136:2377–2395[Abstract]
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