PubMed · 6585571
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J Varga. 1984. Amyloidosis.. https://pubmed.ncbi.nlm.nih.gov/6585571/
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Amylin cosecretes with insulin from pancreatic beta-cells and shows high sequence homology with CGRP, adrenomedullin, and salmon calcitonin. This study aimed to investigate the effect of amylin on the atrial hemodynamics and ANP release from rat atria and to identify its receptor subtypes. Isolated perfused left atria from either control or streptozotocin-treated rats were paced at 1.3 Hz. The concentration of ANP was measured by radioimmunoassay and the translocation of ECF was measured by [3H]-inulin clearance. Rat amylin increased atrial contractility and suppressed the release of ANP. Rat CGRP showed similar effects but was approximately 300-fold more potent than amylin. Pretreatment with receptor antagonist for CGRP1 [rat alpha-CGRP (8-37)] or salmon calcitonin [acetyl-(Asn30, Tyr32)-calcitonin(8-32), (AC 187)] blocked the suppressive effect of ANP release and the positive inotropic effect by rat amylin. However, receptor antagonists for amylin [amylin (8-37), acetyl-amylin] did not block those effects. Amylin (8-37), acetyl-amylin, or rat alpha-CGRP (8-37) alone accentuated the release of ANP with no changes in atrial contractility. The effect of rat amylin and rat amylin (8-37) on the ANP release was attenuated in streptozotocin-treated rats. We suggest that amylin suppressed ANP release with increased atrial contractility through receptors for CGRP1 and salmon calcitonin and the attenuation of amylin and its antagonist on ANP release from streptozotocin-treated rat atria may be due to the downregulation of amylin receptor.
The cystatins were the first amyloidogenic proteins to be shown to oligomerize through a 3D domain swapping mechanism. Here we show that, under conditions leading to the formation of amyloid deposits, the domain-swapped dimer of chicken cystatin further oligomerizes to a tetramer, prior to fibrillization. The tetramer has a very similar circular dichroism and fluorescence signature to the folded monomer and dimer structures, but exhibits some loss of dispersion in the 1H-NMR spectrum. 8-Anilino-1-naphthalene sulfonate fluorescence enhancement indicates an increase in the degree of disorder. While the dimerization reaction is bimolecular and most likely limited by the availability of a predominantly unfolded form of the monomer, the tetramerization reaction is first-order. The tetramer is formed slowly (t(1/2)=six days at 85 degrees C), dimeric cystatin is the precursor to tetramer formation, and thus the rate is limited by structural rearrangement within the dimer. Some higher-order oligomerization events parallel tetramer formation while others follow from the tetrameric form. Thus, the tetramer is a transient intermediate within the pathway of large-scale oligomerization.
The pancreatic hormone amylin (AMY) and the AMY-receptor-agonist salmon-calcitonin (sCT) reduce short-term food-intake after binding to the area postrema (AP), a circumventricular organ (CVO) lacking blood-brain-barrier characteristics. AMY has also been proposed to induce drinking via another CVO, the subfornical organ (SFO). In cellular systems, AMY-binding is generated by interaction of calcitonin-receptor a/b (CT((a))/CT((b))) with receptor-activity modifying proteins (RAMPs). By using in situ hybridization, the codistribution of CT((a))/CT((b)) with RAMP1-3 and c-fos was mapped in CVOs of rats. AMY and sCT induced c-fos within the SFO which contained CT((a)) and/or CT((b)) and RAMP1/2 mRNA. AMY and sCT also activated AP neurons, which express the CT((a)), but not the CT((b)), receptor and RAMP2/3 mRNA. These data emphasize the important role of these structures as primary targets for circulating AMY.