AKAP79 (blue) brings SAP97 (green) to the plasma membrane (bottom), where they also associate with CaN and PKA.

Opposites really do attract. Results on page 101 by Oliveria et al. show that, although they perform opposing functions, a kinase and a phosphatase linked to synaptic plasticity are close neighbors at the plasma membrane. The two are brought together by the scaffolding protein AKAP79 into a complex that may be important for efficient learning.The close proximity of the three proteins is uncovered by a powerful microscopy technique, fluorescence resonance energy transfer (FRET). Using this technique in COS cells, the group shows that protein kinase A (PKA) and the phosphatase calcineurin (CaN) bind to sites on membrane-targeted AKAP79 that are spaced only nanometers apart. In neurons, AKAP79 is known to associate with SAP97, a scaffolding protein that links the signaling complex to glutamate receptors. Now, using standard immunofluorescence techniques, the authors show that expression of SAP97 in COS cells brings a complex of PKA-AKAP-CaN and SAP97 to the plasma membrane.

This complex may also be assembled at synapses in neurons, indicating that scaffolds coordinate colocalization of proteins that do not necessarily interact, but rather regulate common downstream targets—in this case, glutamate receptors. The proximity of the proteins—not necessarily to each other but to their common target—is expected to regulate signaling during long-term potentiation or depression by increasing both efficiency (i.e., cAMP or Ca2+ increases will more rapidly activate PKA or CaN, respectively) and specificity (e.g., only Ca2+ increases that occur near the receptors will activate calcineurin). ▪