Hormone action often requires the mobilization of intracellular second messengers to activate protein kinases and phosphatases. Anchoring proteins provide a molecular framework to orient these enzymes towards selected substrates. Prototypic examples of these "signal-directing molecules" are A-kinase Anchoring Proteins (AKAPs) that sustain multi-protein signaling complexes of the cAMP dependent protein kinase (PKA) and other enzymes. AKAP79 is a multivalent anchoring protein that binds PKA, the calcium/phospholipid dependent kinase (PKC), and the calcium/calmodulin dependent phosphatase (PP2B). During the past funding period we have demonstrated that AKAP79 is recruited into larger signaling networks with individual substrates. This proposal assesses the role of AKAP79 in facilitating PKA and PP2B regulation of AMPA-type glutamate receptor trafficking and PKC mediated suppression of M- type potassium currents.
Aim 1 tests the premise that anchored PKA sustains the surface expression of AMPA receptors whereas PP2B triggers a pathway to signal internalization of the channel. Biochemical and electrophysiological techniques will determine if anchored PKA and PP2B differentially regulate the degradation of PSD-95, an adapter protein that couples AKAP79 to an AMPA receptor subunit.
Aim 2 is derived from preliminary data suggesting that AKAP79 anchors PKC to facilitate muscarinic suppression of M-type potassium channels. RNA inference techniques and the concomitant expression of mutant AKAP forms will determine if PKC anchoring is necessary for agonist dependent and suppression of M currents and if PP2B counteracts this process.
|Sonkusare, Swapnil K; Dalsgaard, Thomas; Bonev, Adrian D et al. (2014) AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal 7:ra66|
|Mercado, Jose; Baylie, Rachael; Navedo, Manuel F et al. (2014) Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle. J Gen Physiol 143:559-75|
|Gold, Matthew G; Fowler, Douglas M; Means, Christopher K et al. (2013) Engineering A-kinase anchoring protein (AKAP)-selective regulatory subunits of protein kinase A (PKA) through structure-based phage selection. J Biol Chem 288:17111-21|
|Scott, John D; Dessauer, Carmen W; Tasken, Kjetil (2013) Creating order from chaos: cellular regulation by kinase anchoring. Annu Rev Pharmacol Toxicol 53:187-210|
|Gold, Matthew G; Reichow, Steve L; O'Neill, Susan E et al. (2012) AKAP2 anchors PKA with aquaporin-0 to support ocular lens transparency. EMBO Mol Med 4:15-26|
|Gold, Matthew G; Stengel, Florian; Nygren, Patrick J et al. (2011) Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex. Proc Natl Acad Sci U S A 108:6426-31|
|Cheng, Edward P; Yuan, Can; Navedo, Manuel F et al. (2011) Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein. Circ Res 109:255-61|
|Hoshi, Naoto; Langeberg, Lorene K; Gould, Christine M et al. (2010) Interaction with AKAP79 modifies the cellular pharmacology of PKC. Mol Cell 37:541-50|
|Por, Elaine D; Samelson, Bret K; Belugin, Sergei et al. (2010) PP2B/calcineurin-mediated desensitization of TRPV1 does not require AKAP150. Biochem J 432:549-56|
|Efendiev, Riad; Samelson, Bret K; Nguyen, Bao T et al. (2010) AKAP79 interacts with multiple adenylyl cyclase (AC) isoforms and scaffolds AC5 and -6 to alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors. J Biol Chem 285:14450-8|
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