Abnormal expression of the cytoskeletal protein dystrophin has deleter
ious consequences for skeletal muscle, cardiac muscle, and the central
nervous system. A complete failure to express the protein produces Du
chenne muscular dystrophy (DMD), in which there is extensive and progr
essive skeletal muscle necrosis, the development of a life-threatening
dilated cardiomyopathy, and mild mental retardation. Dystrophin binds
the F-actin cytoskeleton and is normally expressed in a complex of tr
ansmembrane proteins (the ''dystrophin protein complex'') that interac
t with external components of the basal lamina. One pathogenic model f
or DMD (the ''structural hypothesis'') suggests that this complex form
s a structural bridge between the external basal lamina and the intern
al cytoskeleton and that the absence of dystrophin produces a defect i
n membrane structural support that renders skeletal muscle susceptible
to plasmalemmal ruptures (or ''tears'') during the course of contract
ile activity. This review attempts to critically evaluate the structur
al hypothesis for DMD and presents an opposing model (the ''channel ag
gregation model'') that highlights the role of dystrophin in organizin
g the membrane cytoskeleton and the role of the cytoskeleton in aggreg
ating ion channels and neurotransmitter receptors. Since ion channel a
ggregation is a process that is common across organ systems, the idea
that channel function can be altered when aggregated ion channels inte
ract with a dystrophic cytoskeleton has immediate implications for the
expression of the dystrophinopathies in skeletal muscle, cardiac musc
le, and the central nervous system. (C) 1998 Academic Press.