Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines

Woolfrey, Kevin M.; Srivastava, Deepak P.; Photowala, Huzefa; Yamashita, Megumi; Barbolina, Maria V.; Cahill, Michael E.; Xie, Zhong; Jones, Kelly A.; Quilliam, Lawrence A.; Prakriya, Murali; Penzes, Peter

doi:10.1038/nn.2386

Cited by 152 publications

(230 citation statements)

References 47 publications

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“…Chronic increases in cAMP cause spine shrinkage via activation of the Rap-GEF EPAC2 in cortical cultures (73). None of the PKA activators or inhibitors we used induced changes in spine size or shape (Fig.…”

Section: Discussionmentioning

confidence: 95%

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Lü

Zha

Kim

et al. 2011

Journal of Biological Chemistry

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The A kinase anchor protein AKAP150 recruits the cAMPdependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development.Dendritic spines receive most of the excitatory input in mammalian neurons (1, 2) and compartmentalize signaling that regulates the synaptic response (3, 4). Several protein kinases and phosphatases, including CaMKII, cAMP-dependent protein kinase (PKA), 3 PKC, and protein phosphatase PP2A and PP2B (calcineurin) (5) play prominent roles in synaptic plasticity. Synaptic activity translates into their activation, thereby affecting spine stability, morphology, and postsynaptic responses (6 -13). Spines are dynamically gained and lost during synaptogenesis (9, 14 -16) and in response to neuronal activity (17-19).AKAP150 is a product of the Akap5 gene in mice and is the main AKAP that recruits PKA to postsynaptic sites (20 -25). It binds with its very C terminus to the N-terminal dimerization domain of the regulatory RII subunits of PKA (26,27). It also binds PKC (28), PP2B (29,30), and the SH3-GK region of the postsynaptic scaffolding proteins SAP97 and PSD-95 (31, 32). PSD-95 binds with its PDZ domains to the C-terminal ((S/ T)X(I/V)) motif of NMDA-type glutamate receptor (NMDAR) NR2 subunits (33). PSD-95 also binds to the C terminus of stargazin (␥2) and its homologues ␥3, ␥4, and ␥8, which associate with AMPAR-type glutamate receptor (AMPAR) for postsynaptic localization in conjunction with . SAP97 directly binds to the AMPAR GluR1 subunit via a PDZ-C-terminal interaction (37) to link AKAP150 and thereby PKA, PKC,. Phosphorylation of GluR1 on Ser-845 by PKA can increase channel activity (42) and accumulation of GluR1-containing AMPAR at the postsynaptic site during hippocampal LTP (43, 44) (see also Refs. 45,46). The N terminus of AKAP150 also binds F-actin, cadherin, adenylyl cyclases, and PIP 2 and targets AKAP150 to dendritic spines and the central region binds PSD-...

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Section: Discussionmentioning

confidence: 95%

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Lü

Zha

Kim

et al. 2011

Journal of Biological Chemistry

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“…Among the two known mammalian EPAC isoforms, EPAC1 is ubiquitously expressed in all major tissues, whereas EPAC2 is mainly restricted to the brain, pancreas, and adrenal gland (1,2). Consistent with this tissue-specific expression pattern of EPAC isoforms, EPAC1 has been implicated in cardiac hypertrophy (3,4), fibrosis (5-7), and cancers (8-10), as well as leptin resistance (11), whereas EPAC2 is involved in diabetes/insulin secretion (12)(13)(14)(15)(16)(17)(18) and autism/depression (19)(20)(21).…”

mentioning

confidence: 87%

Isoform-specific antagonists of exchange proteins directly activated by cAMP

Tsalkova

Mei

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

126

148

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The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular cAMP receptors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), as well as cyclic nucleotide-gated ion channels in certain tissues. Although a large number of PKA inhibitors are available, there are no reported EPAC-specific antagonists, despite extensive research efforts. Here we report the identification and characterization of noncyclic nucleotide EPAC antagonists that are exclusively specific for the EPAC2 isoform. These EAPC2-specific antagonists, designated as ESI-05 and ESI-07, inhibit Rap1 activation mediated by EAPC2, but not EPAC1, with high potency in vitro. Moreover, ESI-05 and ESI-07 are capable of suppressing the cAMP-mediated activation of EPAC2, but not EPAC1 and PKA, as monitored in living cells through the use of EPAC-and PKA-based FRET reporters, or by the use of Rap1-GTP pull-down assays. Deuterium exchange mass spectroscopy analysis further reveals that EPAC2-specific inhibitors exert their isoform selectivity through a unique mechanism by binding to a previously undescribed allosteric site: the interface of the two cAMP binding domains, which is not present in the EPAC1 isoform. Isoform-specific EPAC pharmacological probes are highly desired and will be valuable tools for dissecting the biological functions of EPAC proteins and their roles in various disease states.cAMP-regulated guanine nucleotide exchange factor | high-throughput screening | hydrogen/deuterium exchange mass spectrometry

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“…There is increasing evidence that Epac is a mediator of cAMP-dependent changes in hippocampal synaptic plasticity (Gelinas et al, 2008;Whitaker and Wei, 2009;Woolfrey et al, 2009) and memory retrieval (Ostroveanu et al, 2010;Ouyang et al, 2008). Epac also appears to be implicated in the regulation of neurotransmitter release (Gekel and Neher, 2008;Kaneko and Takahashi, 2004) as well as synaptic and spine modulation that are critical for neuronal plasticity (Woolfrey et al, 2009).…”

Section: Implications Of Epac As a Novel Intracellular Signaltransducmentioning

confidence: 99%

“…Epac also appears to be implicated in the regulation of neurotransmitter release (Gekel and Neher, 2008;Kaneko and Takahashi, 2004) as well as synaptic and spine modulation that are critical for neuronal plasticity (Woolfrey et al, 2009). Epac is also emerging as a potential candidate molecule associated with a number of neuropsychiatric disorders.…”

Section: Implications Of Epac As a Novel Intracellular Signaltransducmentioning

confidence: 99%

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

Molosh

Sajdyk

Truitt

et al. 2013

Neuropsychopharmacol

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Neuropeptide Y (NPY) administration into the basolateral amygdala (BLA) decreases anxiety-like behavior, mediated in part through the Y 1 receptor (Y 1 R) isoform. Activation of Y 1 Rs results in G-protein-mediated reduction of cAMP levels, which results in reduced excitability of amygdala projection neurons. Understanding the mechanisms linking decreased cAMP levels to reduced excitability in amygdala neurons is important for identifying novel anxiolytic targets. We studied the intracellular mechanisms of activation of Y 1 Rs on synaptic transmission in the BLA. Activating Y 1 Rs by [Leu 31 ,Pro 34 ]-NPY (L-P NPY) reduced the amplitude of evoked NMDA-mediated excitatory postsynaptic currents (eEPSCs), without affecting AMPA-mediated eEPSCs, but conversely increased the amplitude of GABA A -mediated evoked inhibitory postsynaptic currents (eIPSCs). Both effects were abolished by the Y 1 R antagonist, PD160170. Intracellular GDP-b-S, or pre-treatment with either forskolin or 8Br-cAMP, eliminated the effects of L-P NPY on both NMDA-and GABA A -mediated currents. Thus, both the NMDA and GABA A effects of Y 1 R activation in the BLA are G-protein-mediated and cAMPdependent. Pipette inclusion of protein kinase A (PKA) catalytic subunit blocked the effect of L-P NPY on GABA A -mediated eIPSCs, but not on NMDA-mediated eEPSCs. Conversely, activating the exchange protein activated by cAMP (Epac) with 8CPT-2Me-cAMP blocked the effect of L-P NPY on NMDA-mediated eEPSCs, but not on GABA A -mediated eIPSCs. Thus, NPY regulates amygdala excitability via two signal-transduction events, with reduced PKA activity enhancing GABA A -mediated eIPSCs and Epac deactivation reducing NMDAmediated eEPSCs. This multipathway regulation of NMDA-and GABA A -mediated currents may be important for NPY plasticity and stress resilience in the amygdala.

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Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines

Cited by 152 publications

References 47 publications

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Isoform-specific antagonists of exchange proteins directly activated by cAMP

NPY Y1 Receptors Differentially Modulate GABAA and NMDA Receptors via Divergent Signal-Transduction Pathways to Reduce Excitability of Amygdala Neurons

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