Synaptic plasticity: one STEP at a time

Abstract

Striatal enriched tyrosine phosphatase (STEP) has recently been identified as a crucial player in the regulation of synaptic function. It is restricted to neurons within the CNS and acts by downregulating the activity of MAP kinases, the tyrosine kinase Fyn and NMDA receptors. By modulating these substrates, STEP acts on several parallel pathways that impact upon the progression of synaptic plasticity. Here, we review recent advances that demonstrate the importance of STEP in normal cognitive function, and its possible involvement in cognitive disorders such as Alzheimer's disease.

Figure 1. STEP structure

Alternative splicing produces four STEP isoforms. STEP₄₆ and STEP₆₁ contain the catalytic domain, which is absent from the other two isoforms STEP₃₈ and STEP₂₀. STEP₄₆ is cytosolic while STEP₆₁ is targeted to the endoplasmic reticulum and the postsynaptic density. These two isoforms differ by an additional 172 amino acids at the N-terminus of STEP61. This domain contains two transmembrane (TM) domains, two polyproline and two adjacent PEST domains (PP). The first polyproline domain interacts with Fyn, while the PEST sequences are sites of potential cleavage. Domains that are shared by STEP₄₆ and STEP₆₁ include the binding site for ERK, the kinase interacting motif (KIM), and the approximately 280 amino acid phosphatase domain (PTP) containing an 11 amino acid catalytic site (*). STEP₆₁ has two serine PKA phosphorylation sites (S), whereas STEP₄₆ contains only the one within the KIM domain. Phosphorylation within the KIM domain sterically prevents the association of ERK with STEP, and leads to enzyme inactivation. The second serine site in STEP₆₁ is immediately adjacent to a PEST site, and is thought to facilitate proteolytic cleavage at that site. The functions of STEP₃₈ and STEP₂₀ are not known at present. These two inactive isoforms may function as dominant negative variants that compete with the active STEP variants for substrates and, by binding to these substrates, preserve (or prevent) their tyrosine dephosphorylation. Note that these variants also have a novel C-terminal 10 amino acid sequence (green), introduced by the alternative splicing, of unknown function.

Figure 2. STEP regulation

Dopamine stimulation of D1 receptors leads to cAMP synthesis, PKA activation and phosphorylation of STEP. Phosphorylation of the regulatory serine within the KIM domain prevents STEP from interacting with some substrates, such as ERK. Glutamate stimulation of NMDA receptors allows Ca²⁺ influx and activation of the serine phosphatase calcineurin leading to dephosphorylation of the regulatory KIM domain serine residue and thereby activation of STEP.

Figure 3. STEP dephosphorylates ERK, Fyn and the NMDA receptor complex

ERK, Fyn and the NR2B subunit of the NMDA receptor are potential STEP substrates. Active ERK is required for synaptic plasticity in all brain regions tested to date. In its activated state, ERK (1) phosphorylates cytoskeletal proteins, (2) regulates back-propagating action potentials, (3) stimulates protein synthesis, and (4) activates transcription. These processes work in parallel to promote synaptic plasticity. Fyn activation has also been implicated in synaptic plasticity through a variety of mechanisms including regulation of (5) glutamate receptor trafficking. Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor results in exocytosis of NMDA receptor–containing endosomes.

Figure 4. STEP activation may lead to abnormal NMDA receptor endocytosis in Alzheimer’s disease

Aβ-peptide binding to the α7 nicotinic acetylcholine receptor (α7nAChR) leads to Ca²⁺ influx, calcineurin activation, and STEP dephosphorylation. Dephosphorylation activates STEP, which in turn inactivates Fyn. Fyn has been implicated in the phosphorylation of a regulatory tyrosine (Y¹⁴⁷²) on the NR2B subunit of the NMDA receptor that leads to exocytosis of this receptor. In the absence of Fyn-mediated tyrosine phosphorylation, the NMDA receptor is internalized by endocytosis. Active STEP opposes trafficking to the membrane by dephosphorylating Fyn and dephosphorylating the Y¹⁴⁷² site on the NR2B subunit.