GABAC receptor sensitivity is modulated by interaction with MAP1B.
GABA(C) receptors contain rho subunits and mediate feedback inhibition from retinal amacrine cells to bipolar cells. We previously identified the cytoskeletal protein MAP1B as a rho1 subunit anchoring protein. Here, we analyze the structural basis and functional significance of the MAP1B-rho1 interaction. Twelve amino acids at the C terminus of the large intracellular loop of rho1 (and also rho2) are sufficient for interaction with MAP1B. Disruption of the MAP1B-rho interaction in bipolar cells in retinal slices decreased the EC(50) of their GABA(C) receptors, doubling the receptors' current at low GABA concentrations without affecting their maximum current at high concentrations. Thus, anchoring to the cytoskeleton lowers the sensitivity of GABA(C) receptors and provides a likely site for functional modulation of GABA(C) receptor-mediated inhibition.
Billups
D
D
Laboratory for Molecular Cell Biology, Department of Pharmacology, University College London, London, WC1E 6BT, United Kingdom.
Hanley
J G
JG
Orme
M
M
Attwell
D
D
Moss
S J
SJ
D026921:Amino Acid Transport Systems, Neutral; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D005982:Glutathione Transferase / Q000235:genetics; D018684:Glycine Agents / Q000494:pharmacology; D050487:Glycine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism*; D018080:Receptors, GABA-B; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000493:pharmacokinetics
C101879:(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid; D026921:Amino Acid Transport Systems, Neutral; D002352:Carrier Proteins; D018756:GABA Antagonists; C087200:GABA-C receptor; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D010455:Peptides; D010721:Phosphinic Acids; D011725:Pyridines; D018079:Receptors, GABA; D018080:Receptors, GABA-B; D011993:Recombinant Fusion Proteins; C085284:microtubule-associated protein 1B; D005680:gamma-Aminobutyric Acid; D005982:Glutathione Transferase