Orchestration of synaptic plasticity through AKAP signaling complexes

doi:10.1016/j.neuropharm.2003.09.016

Neuropharmacology

Volume 46, Issue 3, March 2004, Pages 299-310

https://doi.org/10.1016/j.neuropharm.2003.09.016 Get rights and content

Abstract

Significant progress has been made toward understanding the mechanisms by which organisms learn from experiences and how those experiences are translated into memories. Advances in molecular, electrophysiological and genetic technologies have permitted great strides in identifying biochemical and structural changes that occur at synapses during processes that are thought to underlie learning and memory. Cellular events that generate the second messenger cyclic AMP (cAMP) and activate protein kinase A (PKA) have been linked to synaptic plasticity and long-term memory. In this review we will focus on the role of PKA in synaptic plasticity and discuss how the compartmentalization of PKA through its association with A-Kinase Anchoring Proteins (AKAPs) affect PKA function in this process.

Section snippets

Introduction: LTD and LTP in memory

How does the brain store and access memory? One current hypothesis is that memories are formed and stored through a process known as “synaptic plasticity”. This process refers to a lasting up- or down-regulation of synaptic strength following the activation of a synapse (Martin and Morris, 2002). These long-lasting changes in synaptic function are believed to provide, at least in part, the cellular basis of learning and memory (Hebb, 1949, Alkon and Nelson, 1990, Bliss and Collingridge, 1993,

PKA and its role in synaptic plasticity

cAMP is a soluble second messenger expressed in all cell types. Phosphorylation mediated by the cAMP signaling pathway can be elicited by number of different ligands such as neurotransmitters, hormones and growth factors. In addition to synaptic plasticity, cAMP signaling also critically regulates other cellular functions including cell motility, growth, metabolism, and ion channel conductivity (Scott, 1991, Francis and Corbin, 1994). The effect of cAMP is primarily mediated through its target,

The architecture of AKAPs

Since cAMP and PKA are involved in numerous signaling cascades even within the same cellular compartment, what ensures the specificity of action of each cascade? At least part of the regulation of PKA signaling can be attributed to anchoring proteins that localize kinases and phosphatases to their substrates (Pawson and Scott, 1997). In the case of PKA, A-kinase anchoring proteins (AKAPs) function to compartmentalize PKA to distinct subcellular locations (Colledge and Scott, 1999, Bauman and

AKAP79

The capacity of AKAPs to coordinate multienzyme-signaling complexes is exemplified by the neuronal AKAP79 family of anchoring proteins. This family consists of three structurally similar orthologs: AKAP75 (bovine), AKAP150 (mouse), and AKAP79 (human) (Carr et al., 1992). These three proteins are highly related and differ mainly in their molecular weights, a consequence of a repeat sequence present in the N-terminus of AKAP150. These AKAPs are present in the postsynaptic density (PSD) at a

WAVE1

Another AKAP known to assemble and coordinate multi-protein complexes in neurons is WAVE1. WAVE1 belongs to the Wiskott-Aldrich syndrome protein (WASP) family, which includes the WASPs (WASP and N-WASP) and the three SCAR/WAVEs members (WAVE1, WAVE2, and WAVE3). These proteins are cytoplasmic molecules that link Rho GTPases to actin assembly (Machesky and Insall, 1998, Suetsugu et al., 1999, Takenawa and Miki, 2001). The WAVEs share a conserved Verprolin-Cofilin-Acidic (VCA)-rich domain that

Conclusions

The studies summarized in this review indicate that PKA and its AKAPS may be key contributors to the synaptic changes that encode memories. Biochemical, molecular and genetic experiments suggest that the appropriate localization and targeting of PKA via AKAPs is important for regulating PKA activity during synaptic plasticity. AKAP79/150 preferentially targets kinases, such as PKA and PKC, and phosphatases, such as PP2B, to glutamate receptors at the postsynaptic density (Colledge et al., 2000

Acknowledgements

We wish to thank Marcie Colledge, Jennifer Michel, Scott Soderling, and other members of the Scott lab for providing critical evaluation of the manuscript. This work was supported in part through NIH grants NS045513-01 (Andrea L. Bauman) and DK44239 (John D. Scott).

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AKAP79/150 was found to be important in regulating CREB activation, mainly through its binding of PKA. It is interesting to note that apart from AKAP79/150 there are numerous other AKAPs that are expressed in neurons (68–70) that may take on distinct or partially overlapping roles in compartmentalizing PKA activity. Recently, the non-AKAP microtubule-binding protein MAP2 was identified as a major anchoring protein for PKA (type II) in neurons (71).
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It is required for olfactory long-term memory formation (Lu et al., 2007a). Apparently other AKAPs fulfill similar functions in other organisms: A yet unidentified AKAP is necessary for synaptic plasticity in the sea hare (Aplysia californica; Liu et al., 2004a) and many mammalian AKAPs are involved in synaptic function, most importantly AKAP79/150 (Bauman et al., 2004). In Chlamydomonas reinhardtii, a unicellular green alga with two motile flagella, radial spoke protein 3 (RSP3) is the only established nonanimal AKAP (Gaillard et al., 2001).
The second messenger cyclic adenosine monophosphate (cAMP), which is produced by adenylyl cyclases following stimulation of G-protein-coupled receptors, exerts its effect mainly through the cAMP-dependent serine/threonine protein kinase A (PKA). Due to the ubiquitous nature of the cAMP/PKA system, PKA signaling pathways underlie strict spatial and temporal control to achieve specificity. A-kinase anchoring proteins (AKAPs) bind to the regulatory subunit dimer of the tetrameric PKA holoenzyme and thereby target PKA to defined cellular compartments in the vicinity of its substrates. AKAPs promote the termination of cAMP signals by recruiting phosphodiesterases and protein phosphatases, and the integration of signaling pathways by binding additional signaling proteins. AKAPs are a heterogeneous family of proteins that only display similarity within their PKA-binding domains, amphipathic helixes docking into a hydrophobic groove formed by the PKA regulatory subunit dimer. This review summarizes the current state of information on compartmentalized cAMP/PKA signaling with a major focus on structural aspects, evolution, diversity, and (patho)physiological functions of AKAPs and intends to outline newly emerging directions of the field, such as the elucidation of AKAP mutations and alterations of AKAP expression in human diseases, and the validation of AKAP-dependent protein–protein interactions as new drug targets. In addition, alternative PKA anchoring mechanisms employed by noncanonical AKAPs and PKA catalytic subunit-interacting proteins are illustrated.
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ReviewOrchestration of synaptic plasticity through AKAP signaling complexes

Abstract

Section snippets

Introduction: LTD and LTP in memory

PKA and its role in synaptic plasticity

The architecture of AKAPs

AKAP79

WAVE1

Conclusions

Acknowledgements

Cell

J. Biol. Chem.

Cell

Cell

Cell

Mol. Cell Neurosci.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

Neuron

Trends Cell Biol

J. Biol. Chem.

J. Biol. Chem

Neuron

J. Biol. Chem.

FEBS Lett.

Neuron

Neuron

Cell

Neuron

Curr. Biol.

Neuron

Cell

Neuron

FEBS Lett.

Curr. Biol.

Cell

Neuron

Neuron

Trends Biochem. Sci.

Curr. Biol.

Cell

Neuron

Curr. Biol.

Curr. Opin. Neurobiol.

Cell

Neuron

Specificity of molecular changes in neurons involved in memory storage

Faseb. J.

Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons

Science

Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase

J. Neurosci.

Kinase- and phosphatase-anchoring proteins: harnessing the dynamic duo

Nat. Cell Biol.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP

Science

Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase

Proc. Natl. Acad. Sci. USA

Long-term potentiation induced by theta frequency stimulation is regulated by a protein phosphatase-1-operated gate

J. Neurosci.

Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia

Science

Ubiquitin-mediated proteolysis in learning and memory

Mol. Neurobiol.

Molecular analysis of cDNA clones and the corresponding genomic coding sequences of the Drosophila dunce+ gene, the structural gene for cAMP phosphodiesterase

Proc. Natl. Acad. Sci. USA

Review
Orchestration of synaptic plasticity through AKAP signaling complexes