Autoimmune antigen megalin displays similarities with skeletal muscle ryanodine receptor/Ca2+ release channel

Ryanodine receptors are a family of intracellular Ca2+ release channel prot eins, which exist as tetrameric complexes of large (similar to 5000 amino a cid residue) polypeptide monomers. As well as controlling striated muscle c ontraction and neurotransmitter release, these channel proteins have been i mplicated in several pathological states. In order to characterise ryanodin e receptors in various tissues, mouse monoclonal antibodies were developed against the type isoform isolated from skeletal muscle. Several of these an tibodies recognise ryanodine receptor in skeletal muscle, as well as high m olecular weight (k-HMW) protein in kidney microsomes. Like the ryanodine re ceptor, the k-HMW protein binds Ca-45(2+) and sediments as a large complex upon sucrose density-gradient centrifugation. In contrast, the k-HMW protei n does not bind ryanodine and is glycosylated. Furthermore, monoclonal and polyclonal antibodies generated against purified k-HMW protein do not recog nise skeletal muscle ryanodine receptor. Characterisation of a cDNA clone e ncoding part of the k-HMW protein revealed that it is likely to be the rabb it homologue of human megalin, an autoimmune antigen in membranous glomerul onephritis. Potential consequences of immunological similarities between ry anodine receptors and megalin are discussed in terms of autoimmune disease.