Molecular Studies of Calcium Channels and the Dystrophin-Glycoprotein Complex 
in order to study how the ;8-subunit regulates 
Ca^""" channel activity. 
Dystrophin-Glycoprotein Complex 
A third major project in my laboratory is aimed 
at-understanding the function of dystrophin in 
normal muscle and determining how the absence 
of dystrophin leads to Duchenne muscular dys- 
trophy (DMD). Dystrophin is localized to the in- 
ner surface of the sarcolemma in normal muscle 
but is absent in skeletal muscle of DMD patients 
and mdx mice. We previously showed that dys- 
trophin is tightly linked to a large oligomeric 
complex of sarcolemmal glycoproteins. We have 
isolated a dystrophin-glycoprotein complex and 
have shown that it consists of cytoskeletal, trans- 
membrane, and extracellular components. These 
data have allowed us to propose a model for the 
organization of the dystrophin-glycoprotein 
complex (see figure). The membrane organiza- 
tion of the dystrophin-glycoprotein complex and 
the high density of dystrophin in the sarcolemma 
membrane suggest that this complex could have 
an important structural role in skeletal muscle. 
In the past year we have investigated the rela- 
tive abundance of each of the components of the 
dystrophin-glycoprotein complex in skeletal 
muscle from normal and mdx mice. Our results 
demonstrate that all of the dystrophin-associated 
glycoproteins (DAGs) are significantly reduced 
in mdx skeletal muscle and suggest that the loss 
of DAGs is due to the absence of dystrophin and 
not to secondary effects of muscle fiber degrada- 
tion. Furthermore, we recently showed that the 
absence of dystrophin in skeletal muscle from 
DMD patients leads to a dramatic loss of all the 
components of the dystrophin-glycoprotein com- 
plex. Thus the abnormal expression of the DAGs 
may play a crucial role in molecular pathogenesis 
in DMD. 
In order to identify the normal function of 
the DAGs, we recently established, by cDNA 
cloning, the primary sequence of two compo- 
nents of the dystrophin-glycoprotein complex. 
The 43- and 1 56-kDa DAGs are encoded by the 
same mRNA, and post-translational modifica- 
tion of a 97-kDa precursor protein results in 
two mature proteins: the transmembrane 43- 
kDa DAG and the extracellular 1 56-kDa DAG. 
In addition, we have shown that the 1 56-kDa 
DAG binds laminin, a well-characterized com- 
ponent of the extracellular matrix. Our results 
demonstrate that the 43/1 56-kDa DAG (named 
dystroglycan) is a novel laminin-binding glyco- 
protein and suggest that the function of the 
dystrophin-glycoprotein complex is to provide 
a linkage between the subsarcolemma cytoskel- 
eton and the extracellular matrix. Our findings 
strongly support the hypothesis that in DMD a 
dramatic reduction in a 1 56-kDa DAG leads to 
the loss of a linkage between the sarcolemma 
and extracellular matrix. This may render mus- 
cle fibers more susceptible to necrosis or may 
disrupt the integrity of muscle. 
Our goal for the next year is to clone the other 
DAGs in order to express the entire complex in 
nonmuscle cells to study its function. We also 
plan to examine the possible involvement of the 
DAGs in other muscular dystrophies. 
This work was also supported by the Muscular 
Dystrophy Association. 
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