RESEARCH

Regulation of Membrane Specializations by Protein Scaffolds: Implications for Human Diseases

Spatial integration of molecular signaling is key to rapid and precise communication between cells in all tissues. Many membrane receptors and channels are highly concentrated into specialized membrane domains where rapid and specific signaling is required. These molecular specializations depend on protein scaffolds that cluster surface membrane receptors and organize downstream signaling elements. Genetic abnormalities in protein scaffolds can lead to human diseases.

Our laboratory studies the dystrophin complex, a structural and signaling complex that is especially important in skeletal muscle. Mutations in various proteins of the dystrophin complex cause human muscular dystrophies. We study the dystrophin signaling scaffold primarily at three membrane specializations: the neuromuscular synapse, the muscle sarcolemmal membrane and the endfeet of perivascular astrocytes in the brain. Our main focus is the syntrophins, a family of adapter proteins that we first discovered in 1987, and the dystrobrevins. Both syntrophin and dystrobrevin are directly associated with dystrophin. The syntrophins, in turn, recruit several important signaling proteins and channels to the membrane, including neuronal nitric oxide synthase (nNOS), sodium and potassium channels, aquaporin water channels, several kinases, the ABCA1 lipid transporter, and the ARMS/EphA4 receptor complex. We use molecular biology and biochemistry to study this complex in vitro and genetic manipulation (targeted gene deletion and transgenic expression) in mice to determine in vivo function.

At the neuromuscular synapse, α-syntrophin regulates postsynaptic nicotinic receptor expression and distribution. On the muscle sarcolemma, α-syntrophin is required for expression of nNOS and aquaporin-4. At perivascular astroglial endfeet (an important cellular component of the blood brain barrier), α-syntrophin is required for the maintenance of high concentrations of aquaporin-4 water channels. As a result, α-syntrophin null mice are resistant to brain edema and neuronal damage that follow ischemic insults, such as stroke. Our investigations of the dystrophin complex, and the dystrobrevin-syntrophin subcomplex in particular, have particular relevance to several diseases and human maladies, including muscular dystrophy, stroke, brain edema, epilepsy, and cardiovascular impairment.