How Do Myocytes Tell Right From Left?

Abstract

See related article, pages 646–655 Two cardiomyopathies ascribed to desmosomal mutations have been described: Naxos disease which gives rise to arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C),1 and Carvajal syndrome,2 in which the cardiac pathology is primarily left-sided. How do mutations in a single junctional type lead to such disparate results? In this edition of Circulation Research , Yang et al3 describe a novel desmosomal protein mutation that may shed some light on this perplexing question. Desmosomes were originally given the name “mechanical” or “attachment junctions” describing what was thought to be their main role, cell stabilization. They were called the “glue” that held the tissue together. It has long been assumed that the loss of the “glue” causes disease by providing weak cell–cell interactions in tissues that require strong connections. Desmosomes are comprised of multiple proteins which interact to form a macromolecular complex4 that links the intermediate filaments (desmin in cardiac myocytes) of one cell to the intermediate filaments of the adjacent cells through the transmembrane proteins (Figure, A). The transmembrane domain portion is formed from 2 distinct cadherin proteins, desmocollin and desmoglein which bind to the intracellular linker protein, plakoglobin. Then, via its amino-terminal domain, desmoplakin binds to plakoglobin. The link to the cytoskeleton occurs with the binding of the intermediate filaments with the carboxyl-terminal domain of desmoplakin, an event required for tissue stability. Another cohort protein, plakophilin, also binds plakoglobin and is thought to be important in desmosomal stability. Some component proteins of the desmosome have been shown to be involved in signal transduction, with …