Abstract
A-kinase anchoring proteins (AKAPs) act as scaffolding proteins that bring enzymes involved in cell signaling, such as cyclic-AMP-dependent protein kinase (PKA), calcium- and phospholipid-dependent kinase (PKC), and calcium-calmodulin-dependent phosphatase (PP2B), into proximity with their targets (see Chen and Kass). Noting that AKAPs regulate the phosphorylation status and activity of various ion channels, including AMPA-type glutamate receptors and M-type potassium channels, Hoshi et al. combined RNA interference (RNAi) with expression of AKAP mutants that were unable to bind selected enzymes to investigate the mechanisms underlying specificity of AKAP activity. Knockdown of AKAP79 (human AKAP) in HEK293 cells that expressed the GluR1 subunit of the AMPA-type glutamate receptor attenuated agonist-dependent rundown of GluR1 currents. Rundown was rescued by expression of murine AKAP (AKAP150) or AKAP mutants that lacked the ability to bind PKA or PKC. In contrast, AKAP150 that lacked the ability to bind PP2B failed to rescue agonist-mediated current rundown. Similar results were seen on AMPA currents in rat hippocampal neurons in which AKAP150 was knocked down and was rescued with different forms of AKAP79. Experiments in which the effects of PKA inhibition in cells expressing wild-type AKAP were compared with those in cells expressing the mutant that could not bind PKA indicated that PKA was required for maintenance of the AMPA current. In contrast, muscarinic inhibition of the M current depended on the ability of AKAP to bind PKC. Thus, the same scaffolding protein (AKAP) modulates different targets by assembling elements of distinct signaling pathways. N. Hoshi, L. K. Langeberg, J. D. Scott, Distinct enzyme combinations in AKAP signalling complexes permit functional diversity. Nat. Cell Biol. 7 , 1066-1073 (2005). [PubMed] L. Chen, R. S. Kass, A-kinase anchoring proteins: Different partners, different dance. Nat. Cell Biol. 7 , 1050-1051 (2005). [Online Journal]
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