How Ca2+-permeable AMPA receptors, the kinase PKA, and the phosphatase PP2B are intertwined in synaptic LTP and LTD

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Science Signaling  26 Apr 2016:
Vol. 9, Issue 425, pp. pe2
DOI: 10.1126/scisignal.aaf7067


  • Fig. 1 The AMPAR–β2 adrenergic receptor signaling complex.

    The AMPAR GluA1 subunit is phosphorylated on Ser845 in its cytosolic C terminus by PKA. For fast, effective, and selective signaling, PKA, its upstream regulator adenylyl cyclase (AC), and its antagonist PP2B are linked to GluA1 via AKAP150 and SAP97. The β2 adrenergic receptor is connected to GluA1 via PSD-95 and the auxiliary AMPAR subunits known as TARP or γ subunits. How the trimeric G protein—consisting of an α, a β, and a γ subunit—preassociates with AMPARs is not yet known. CREDIT: P. HUEY/SCIENCE SIGNALING

  • Fig. 2 Temporary recruitment of CP-AMPARs during LTD.

    (A) In response to 1-Hz stimulation, Ca2+ influx through NMDARs triggers LTD. Although how precisely Ca2+ induces LTD is unknown, given that ~50% of NMDAR-dependent LTD requires PKA, Ca2+ might act by activating the Ca2+-sensitive adenylyl cyclases AC1 or AC8. Then, PKA linked to GluA1 via SAP97 and AKAP150 (Fig. 1) phosphorylates GluA1 on Ser845, which promotes the accumulation of GluA1-containing AMPARs and especially of GluA1 homomers at perisynaptic sites (arrow 1). An additional signaling mechanism might involve activation of CaMKII, which then promotes accumulation of GluA1 homomers at postsynaptic sites (arrow 2), possibly via phosphorylation of the C termini of auxiliary γ subunits, which traps AMPARs that include GluA1 homomers at postsynaptic sites [CaMKII and phosphorylation of γ subunits are not depicted in the figure; for details see (26)]. In parallel, the 1-Hz stimulation triggers endocytosis of CI-AMPARs (mostly GluA1/GluA2 heteromeric AMPARs; arrow 3), presumably independently of PP2B. (B) As CP-AMPARs accumulate during LTD induction, they mediate Ca2+ influx, which stimulates PP2B. Like PKA, PP2B is also linked to GluA1 via SAP97 and AKAP150. It dephosphorylates the CP-AMPARs to promote their removal during the later phase of LTD. CREDIT: P. HUEY/SCIENCE SIGNALING

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