Pore formation by beta-2-microglobulin: A mechanism for the pathogenesis of dialysis associated amyloidosis

• Published in: Amyloid 2001, Vol.8 (2), p.94-100
• Main Authors: Hirakura, Yutuka, Kagan, Bruce L.
• Format: Article
• Language: English
• Subjects: Amyloidosis - etiology; Amyloidosis - metabolism; beta 2-Microglobulin - metabolism; beta-2-microglobulin; Congo Red - pharmacology; dialysis amyloidosis; Humans; Ion Channels - antagonists & inhibitors; Ion Channels - metabolism; Membrane Potentials; pore formation; Protein Structure, Secondary; Renal Dialysis - adverse effects; Zinc - pharmacology
• ISSN: 1350-6129; 1744-2818
• DOI: 10.3109/13506120109007350

Beta-2 microglobulin (β2M, molecular weight 10,000) is a 99 residue immune system protein which is part of the MHC Class I complex whose role is to present antigens to T cells. β2M serum levels rise dramatically in renal failure, and a syndrome called "dialysis associated amyloidosis" occurs with time in a majority of hemodialysis patients who exhibit β2M amyloid deposits in joints, bone and other organs1. β2McAn also induce Ca++ efflux from calvariae, collagenase production, and bone resorption2-4. We report here that β2M formed relatively nonselective, long-lived, voltage independent ion channels in planar phospholipid bilayer membranes at physiologically relevant concentrations. The channels were inhibited by Congo red and blocked by zinc suggesting that they exist in an aggregated beta sheet state as is common with other amyloid fibril forming peptides. Multiple single channel conductances were seen suggesting that various oligomers of β2M may be capable of forming channel structures. We suggest that β2M channel formation may account for some of the pathophysiologic effects seen in dialysis associated amyloidosis. These findings lend further weight to the "channel hypothesis" of amyloid pathogenesis.