Schematic diagram of InaD and NHERF, illustrating the protein–protein interactions mediated by these two PDZ proteins. (a) InaD binds to the G protein (Gqα)–linked receptor rhodopsin (Rh), the light-activated cation channels TRP and TRPL, phospholipase C-β (PLC), and protein kinase C (PKC) via PDZ domains. Calmodulin binds to the region between PDZ1 and PDZ2. A higher-order structure is organized at the plasma membrane by homomeric and heteromeric binding between PDZ domains 3 and 4. Reproduced, with permission, from ref. 9. (b) The β2-adrenergic receptor binds to the first PDZ domain of NHERF, and the Na+/H+ exchanger NHE-3 binds to a region adjacent to and including the second PDZ domain. Ezrin binds to a domain in the COOH-terminus of NHERF, linking the protein complex to the actin cytoskeleton and protein kinase A (PKA-II). Both PKA-II and the β2-adrenergic receptor regulate the activity of NHE-3.