Down-regulation of rat kidney calcitonin receptors by salmon calcitonin infusion evidenced by autoradiography.

Abstract

In treating age-related osteoporosis and Paget disease of bone, it is of major importance to avoid an escape phenomenon that would reduce effectiveness of the treatment. The factors involved in the loss of therapeutic efficacy with administration of large pharmacological doses of the hormone require special consideration. Down-regulation of the hormone receptors could account for the escape phenomenon. Specific binding sites for salmon calcitonin (sCT) were characterized and localized by autoradiography on rat kidney sections incubated with 125I-labeled sCT. Autoradiograms demonstrated a heterogenous distribution of 125I-labeled sCT binding sites in the kidney, with high densities in both the superficial layer of the cortex and the outer medulla. Infusion of different doses of unlabeled sCT by means of Alzet minipumps for 7 days produced rapid changes in plasma calcium, phosphate, and magnesium levels, which were no longer observed after 2 or 6 days of treatment. Besides, infusion of high doses of sCT induced down-regulation of renal sCT binding sites located mainly in the medulla, where calcitonin (CT) has been shown to exert its physiological effects on water and ion reabsorption. These data suggest that the resistance to high doses of sCT often observed during long-term treatment of patients may be the consequence of not only bone-cell desensitization but also down-regulation of CT-sensitive kidney receptor sites.

Enhancement of 1,25-dihydroxyvitamin D3-mediated suppression of experimental autoimmune encephalomyelitis by calcitonin

“…Consistent with previous reports, CT treatment caused a transient decrease in serum calcium levels, which returned to baseline levels within 48 h (31). The transient nature of the hypocalcemic effect by CT has been attributed to down-regulation of the CT receptor by CT itself (32). Surprisingly, when CT was delivered in combination with a subtherapeutic dose of 1,25(OH) 2 D 3 , it significantly enhanced the suppression of EAE by 1,25(OH) 2 D 3 .…”

Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

“…Post hoc testing revealed this occurred on all five injection days and on postinjection days 1 and 2 (P Ͻ 0.05). There was also a significant overall effect of sCT on meal frequency [F (8,16) ϭ 3.6, P Ͻ 0.05]. For the monkeys that ate, the latency to first meal [F (8, 16) ϭ 1.5, n.s.]…”

“…Sustained peripheral 7-day infusions of sCT have been shown to cause a dose-dependent decrease in renal calcitonin-binding sites (8). The inability to demonstrate behavioral tolerance and the prolonged suppression of sCT on the food intake following termination, however, suggests a continued activation of the CTR/RAMP1 downstream effects (17).…”

Amylin: Pharmacology, Physiology, and Clinical Potential

“…However, there is evidence that the calcitonin receptor can be regulated by these mechanisms in a cell-and ligand-dependent manner. The calcitonin receptor is also subject to downregulation, influencing the utility of calcitonin agonists as drugs for bone diseases (Tashjian et al, 1978;Bouizar et al, 1987). Although it is tempting to infer that amylin receptors will behave similarly, these processes are highly dependent on cellular context; thus, how the calcitonin receptor behaves in osteoclasts is unlikely to translate directly to other cell types, such as AP neurons.…”