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Neurobiology Unit, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia
The structure/function relationship of salmon calcitonin (sCT)
analogues was investigated in heterologous calcitonin receptor (CTR)
expression systems. sCT analogues with progressive amino-terminal truncations intermediate of sCT-(1-32) to sCT-(8-32) were examined for their ability to act as agonists, antagonists, or inverse agonists.
Two CTR cell clones, B8-H10 and G12-E12, which express ~5 million and
25,000 C1b receptors/cell, respectively, were used for this study. The
B8-H10 clone has an ~80-fold increase in basal levels of
intracellular cAMP due to constitutive activation of the overexpressed
receptor. In whole-cell competition binding studies, sCT-(1-32) was
more potent than any of its amino-terminally truncated analogues in
competition for 125I-sCT binding. In cAMP accumulation
studies, sCT-(1-32) and modified analogues sCT-(2-32) and sCT-(3-32)
had agonist activities. SDZ-216-710, with an amino-terminal truncation
of four amino acids, behaved as a partial agonist/antagonist, whereas
amino-terminal truncations of six or seven amino acid residues produced
a 16-fold reduction in basal cAMP levels and attenuated the response to
the agonist sCT-(1-32) in the constitutively active CTR system. This
inverse agonist effect was insensitive to pertussis toxin inhibition. In contrast, the inverse agonist activity of these peptides was not
observed in the nonconstitutively active CTR system, in which sCT
analogues with amino-terminal truncations of four or more amino acids
behaved as neutral competitive antagonists. These results suggest that
the inverse agonist activity is mediated by stabilization of the
inactive state of the receptor, which does not couple to G protein, and
attenuates basal signaling initiated by ligand-independent activation
of the effector adenylyl cyclase.
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