AKAP Signaling Complexes in Regulation of Excitatory Synaptic Plasticity

Abstract

Plasticity at excitatory glutamatergic synapses in the central nervous system is believed to be critical for neuronal circuits to process and encode information allowing animals to perform complex behaviors such as learning and memory. In addition, alterations in synaptic plasticity are associated with human diseases including Alzheimer's, epilepsy, chronic pain, drug addiction, and schizophrenia. Long-term potentiation (LTP) and depression (LTD) in the hippocampal region of the brain are two forms of synaptic plasticity that increase or decrease, respectively, the strength of synaptic transmission by postsynaptic AMPA-type glutamate receptors. Both LTP and LTD are induced by activation of NMDA-type glutamate receptors but differ in the level and duration of Ca2+ influx through the NMDA receptor and the subsequent engagement of downstream signaling by protein kinases including PKA, PKC, and CaMKII and phosphatases including PP1 and calcineurin-PP2B (CaN). This review addresses the important emerging roles of the A-kinase anchoring protein (AKAP) family of scaffold proteins in regulating localization of PKA and other kinases and phosphatases to postsynaptic multi-protein complexes that control NMDA and AMPA receptor function during LTP and LTD.

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

“…Consequently, PKA phosphorylation events that augment AQP2 pore function must proceed through other AKAP-associated pools of this kinase. Likely candidates include AKAP18δ, a PKAanchoring protein that codistributes, but does not interact with, AQP2, and AKAP79/150 that tethers PKA to membrane-proximal regions (48)(49)(50)(51). There is clear precedent for AKAPs that participate in PKA-independent signaling events.…”

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

“…The PKA-PKC-CaN complex assembled by A-kinase anchoring protein (AKAP) 79/150 (human 79/rodent 150; also known as AKAP5) is a prototypical example of a postsynaptic scaffold-organized signaling complex ( Fig. 2) (13).…”

“…Importantly, this inhibition of AKAP79/150 membrane targeting during LTD may prevent PKA-mediated re-phosphorylation of GluA1 that would promote recycling and reverse LTD (reviewed in Ref. 13). Interestingly, changes in AKAP79/150 synaptic localization, PKA and CaN signaling, and GluA1 Ser-845 phosphorylation have also recently been implicated in regulating GluA1 synaptic localization during slower, homeostatic forms of synaptic plasticity that scale synaptic strength up or down across all inputs in response to chronic increases or decreases in overall neuronal activity, respectively (42,43).…”

Synaptic NMDA receptor stimulation activates PP1 by inhibiting its phosphorylation by Cdk5

“…Protein phosphorylation and dephosphorylation is known to play a critical role in many aspects of neuronal function, including in key steps that are involved in both strengthening and weakening of synaptic communication (Colbran, 2004;Lee, 2006;Sanderson and Dell'Acqua, 2011;Lisman et al, 2012). For example, the serine/threonine protein phosphatase PP1 is enriched in dendritic spines at excitatory synapses (Ouimet et al, 1995;Strack et al, 1999;Terry-Lorenzo et al, 2000), and it controls synaptic plasticity through its ability to dephosphorylate important substrates at the synapse, including Ser845 of the GluA1 -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and Thr286 of CaM kinase II (Bito et al, 1996;Strack et al, 1997;Genoux et al, 2002;Hsieh-Wilson et al, 2003;Hu et al, 2007), and substrates in the nucleus such as the transcription factor CREB (Bito et al, 1996).…”