Adenylyl Cyclase Anchoring by a Kinase Anchor Protein AKAP5 (AKAP79/150) Is Important for Postsynaptic β-Adrenergic Signaling

Yang K Xiang,Minh Nguyen,Tommaso Patriarchi,Hai Qian,Ivar S Stein,Lucas Matt,Johannes W Hell,Mingxu Zhang

doi:10.1074/jbc.m112.449462

Yang K Xiang, Minh Nguyen + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m112.449462

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Abstract

Recent evidence indicates that the A kinase anchor protein AKAP5 (AKAP79/150) interacts not only with PKA but also with various adenylyl cyclase (AC) isoforms. However, the physiological relevance of AC-AKAP5 binding is largely unexplored. We now show that postsynaptic targeting of AC by AKAP5 is important for phosphorylation of the AMPA-type glutamate receptor subunit GluA1 on Ser-845 by PKA and for synaptic plasticity. Phosphorylation of GluA1 on Ser-845 is strongly reduced (by 70%) under basal conditions in AKAP5 KO mice but not at all in D36 mice, in which the PKA binding site of AKAP5 (i.e. the C-terminal 36 residues) has been deleted without affecting AC association with GluA1. The increase in Ser-845 phosphorylation upon β-adrenergic stimulation is much more severely impaired in AKAP5 KO than in D36 mice. In parallel, long term potentiation induced by a 5-Hz/180-s tetanus, which mimics the endogenous θ-rhythm and depends on β-adrenergic stimulation, is only modestly affected in acute forebrain slices from D36 mice but completely abrogated in AKAP5 KO mice. Accordingly, anchoring of not only PKA but also AC by AKAP5 is important for regulation of postsynaptic functions and specifically AMPA receptor activity.

Highlights

AKAP5 is emerging as an adenylyl cyclase (AC)-binding protein
We show that postsynaptic targeting of AC by AKAP5 is important for phosphorylation of the AMPA-type glutamate receptor subunit GluA1 on Ser-845 by PKA and for synaptic plasticity
AKAP5 Is Necessary for AC-GluA1 Interaction—Because AKAP5 interacts with PKA and with at least six AC isoforms (10 –12), we hypothesized that the previously described association of GluA1-containing AMPA receptors with AC [5] is mediated by AKAP5, which in turn is linked to GluA1 via SAP97 and possibly postsynaptic density (PSD)-95 (Fig. 1)

Summary

Background

AKAP5 is emerging as an adenylyl cyclase (AC)-binding protein. Results: Knockout of AKAP5 affects ␤-adrenergic postsynaptic signaling more than abrogating PKA targeting only in AKAP5 deletion mutants. We showed previously that the AMPA-type glutamate receptor subunit GluA1 as well as the L-type Ca2ϩ channel Cav1.2 form complexes with the ␤2-adrenergic receptor (␤2-AR) and PKA that contain one or more AC isoforms along with the AC-stimulating trimeric Gs protein [3,4,5] (see Ref. 6 and Fig. 1) These interactions result in highly localized phosphorylation and regulation of Cav1.2 and GluA1 [3,4,5]. The physiological relevance of the AC-AKAP5-GluA1 interaction remained unexplored This issue is important because, on one hand, association with AKAP5-PKA inhibits the activity of AC2, AC5, and AC6 (but not AC1, AC8, and AC9) [10], whereas, on the other hand, placing ACs in close proximity to PKA-substrate complexes should increase efficacy of the corresponding cAMP-stimulated phosphorylations [12]. We conclude that anchoring of AC by AKAP5 is important for positive regulation of postsynaptic functions that include AMPA receptor activity by cAMP-PKA signaling

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RESULTS

DISCUSSION