Dystrophin-associated protein scaffolding in brain requires alpha-dystrobrevin.

Dystrophin and the alpha-dystrobrevins bind directly to the adapter protein syntrophin to form membrane-associated scaffolds. At the blood-brain barrier, alpha-syntrophin colocalizes with dystrophin and the alpha-dystrobrevins in perivascular glial endfeet and is required for localization of the water channel aquaporin-4. Earlier we have shown that localization of the scaffolding proteins gamma2-syntrophin, alpha-dystrobrevin-2, and dystrophin to glial endfeet is also dependent on the presence of alpha-syntrophin.

gamma-Syntrophin scaffolding is spatially and functionally distinct from that of the alpha/beta syntrophins.

The syntrophins are a family of scaffolding proteins with multiple protein interaction domains that link signaling proteins to dystrophin family members. Each of the three most characterized syntrophins (alpha, beta1, beta2) contains a PDZ domain that binds a unique set of signaling proteins including kinases, ion and water channels, and neuronal nitric oxide synthase (nNOS). The PDZ domains of the gamma-syntrophins do not bind nNOS.

Assembly of a perivascular astrocyte protein scaffold at the mammalian blood-brain barrier is dependent on alpha-syntrophin.

alpha-Syntrophin, a member of the dystrophin-associated protein complex, is required for proper localization of the water channel aquaporin-4 at the blood-brain barrier. Mice lacking alpha-syntrophin have reduced levels of aquaporin-4 in perivascular astroglial endfeet. Consequently, they exhibit reduced edema and infarct volume in brain trauma models and reduced K+ clearance from the neuropil, leading to increased seizure susceptibility.