Editors' ChoiceNeuroscience

GPCR Regulation of BBB Permeability

Science's STKE  18 Oct 2005:
Vol. 2005, Issue 306, pp. tw364
DOI: 10.1126/stke.3062005tw364

The blood-brain barrier (BBB), which in mammals is formed by the tight junctions between the endothelial cells lining the brain capillaries, not only keeps toxins and pathogens out of the brain but also blocks movement of potentially therapeutic drugs and is thus a target for therapeutic intervention. However, little is known about its regulation. The Drosophila BBB, established by septate junctions between surface glia, has recently emerged as a model for the mammalian BBB (see Daneman and Barres). Now, two groups have identified the orphan G protein-coupled receptor (GPCR) Moody as having a critical role in establishing and maintaining the Drosophila BBB.

Schwabe et al. identified Moody as a glial gene in a screen that combined fluorescence-activated cell sorting (FACS) of green fluorescent protein (GFP)-labeled embryonic glia with microarray analysis. The authors used RNA in situ analysis and immunohistochemistry to show that moody was expressed in surface glia, as were Gαi, Gαo, and the RGS protein loco. GFP-labeled Loco localized with labeled Moody at the plasma membrane and interacted with Gi and Go when expressed in cultured S2 cells. Using a dye penetration assay, the authors showed that all four proteins were required for effective insulation by surface glia, with downstream signaling mediated through a common pathway primarily by way of activated Go and Gβγ. Phenotypic analysis of moody and loco loss-of-function mutants and of Gi overexpression indicated that disruption of the Moody signaling pathway led to disruption of the cortical actin cytoskeleton, changes in cell shape, and shortening of the septate junctions.

Intriguingly, Bainton et al. identified moody in a screen for Drosophila mutants with altered cocaine sensitivity: The moody mutants showed increased sensitivity to cocaine and nicotine but decreased sensitivity to ethanol. The authors showed that moody encoded two GPCRs, Moody-α and Moody-β, that differed in their cytoplasmic C-terminal domains and were colocalized in surface glia. Transient inhibition of moody expression in adult flies reversibly disrupted BBB function (assessed by dye penetration), implicating moody in maintenance of the BBB as well as in its establishment. Although expression of either Moody-α or Moody-β was sufficient for normal BBB function, expression of both was required for normal sensitivity to cocaine. Thus, the Moody pathway may provide a target for therapeutic disruption of the BBB and has revealed an unexpected link between the BBB and drug sensitivity.

T. Schwabe, R. J. Bainton, R. D. Fetter, U. Heberlein, U. Gaul, GPCR signaling is required for blood-brain barrier formation in Drosophila. Cell 123, 133-144 (2005). [PubMed]

R. J. Bainton, L. T.-Y. Tsai, T. Schwabe, M. DeSalvo, U. Gaul, U. Heberlein, moody encodes two GPCRs that regulate cocaine behaviors and blood-brain barrier permeability in Drosophila. Cell 123, 145-156 (2005). [PubMed]

R. Daneman, B. A. Barres, The blood-brain barrier: Lessons from moody flies. Cell 123, 9-12 (2005). [PubMed]