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

Abstract. Ryanodine receptors are a family of intracellular Ca²⁺ release channel proteins, which exist as tetrameric complexes of large (∼5000 amino acid residue) polypeptide monomers. As well as controlling striated muscle contraction and neurotransmitter release, these channel proteins have been implicated in several pathological states. In order to characterise ryanodine receptors in various tissues, mouse monoclonal antibodies were developed against the type 1 isoform isolated from skeletal muscle. Several of these antibodies recognise ryanodine receptor in skeletal muscle, as well as high molecular weight (k-HMW) protein in kidney microsomes. Like the ryanodine receptor, the k-HMW protein binds ⁴⁵Ca²⁺ and sediments as a large complex upon sucrose density-gradient centrifugation. In contrast, the k-HMW protein docs not bind ryanodine and is glycosylated. Furthermore, monoclonal and polyclonal antibodies generated against purified k-HMW protein do not recognise skeletal muscle ryanodine receptor. Characterisation of a cDNA clone encoding part of the k-HMW protein revealed that it is likely to be the rabbit homologue of human megalin, an autoimmune antigen in membranous glomerulonephritis. Potential consequences of immunological similarities between ryanodine receptors and megalin are discussed in terms of autoimmune disease.