DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons

Abstract

Environmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments' fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.

Actin cytoskeleton in dendritic spine development and plasticity

“…Alternatively, adducins could function in activity-dependent barbed end capping as they cap the barbed end of actin filaments and cross-link them with the spectrin cytoskeleton [49]. β-adducin is localized to dendritic spines and mice lacking β-adducin display impaired synaptic plasticity, motor coordination and learning deficits [50–53]. Modulation and specificity of capping activity amongst these various classes of barbed end capping proteins is likely specified by binding partners, differential affinity for barbed ends, other actin-regulatory domains within the protein (such as bundling or severing) and post-translational modifications.…”

DARPP‐32 in the orchestration of responses to positive natural stimuli

“…Adducins are actin‐capping proteins that stabilize the cortical cytoskeleton and regulate synaptic stability (Engmann et al . ). In particular, β‐adducin is essential for the stability of dendritic spines and is involved in learning and memory processes through the regulation of actin‐ and spectrin‐based synapse formation (Bednarek and Caroni ; Pielage et al .…”

Glutamate Counteracts Dopamine/PKA Signaling via Dephosphorylation of DARPP-32 Ser-97 and Alteration of Its Cytonuclear Distribution

“…C-E, immunohistochemical analysis of P-ERK in the dorsal striatum (C), NAc core (D), and NAc shell (E) from wild type and S97A mice. mechanism (10) and also by decreased binding to adducin, which is a cytoplasmic partner (11). However, in contrast to the nuclear accumulation of phospho-Thr-34 DARPP-32 observed after activation of PKA signaling, following glutamate signaling, dephospho-Thr-34 DARPP-32 accumulates in the nucleus (Fig.…”

“…Subsequent studies revealed that Ser-97 phosphorylation of DARPP-32 acts in conjunction with a nuclear export signal to facilitate export of DARPP-32 from the nucleus (10). In addition, phosphorylation of Ser-97 increases the interaction of DARPP-32 with adducin, a protein associated with cortical actin-spectrin cytoskeleton (11). The results from the current study suggest that glutamate can act via AMPA and/or NMDA receptors to induce the dephosphorylation of DARPP-32 at Ser-97 by PP2A/PR72.…”

“…Notably, PKA activation also induces dephosphorylation of DARPP-32 at Ser-97 by PP2A/B56␦, resulting in nuclear accumulation of phospho-Thr-34/dephospho-Ser-97 DARPP-32, leading to PP1 inhibition in the nucleus, histone H3 phosphorylation, and transcriptional activation (10). Phosphorylation of Ser-97 also increases interaction of DARPP-32 with adducin and can thus facilitate its regulation by DARPP-32 (11). PP2C is also implicated in the dephosphorylation of DARPP-32 at Thr-75 (6) and Ser-130 (9).…”