Knockout of STriatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation

Venkitaramani, Deepa V.; Paul, Surojit; Zhang, Yongfang; Kurup, Pradeep; Ding, Li; Tressler, Lyal; Allen, Martin P.; Sacca, Rosalba; Picciotto, Marina R.; Lombroso, Paul J.

doi:10.1002/syn.20608

Cited by 83 publications

(119 citation statements)

References 26 publications

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“…To extend these initial findings, we next examined the effect of various concentrations of ethanol (40,80, and 120 mM) on NMDAR EPSCs in STEP KO mice (21). These results show that 80 and 120 mM produced significant inhibition of the NMDAR currents from WT neurons, but none of the ethanol concentrations tested inhibited the NMDAR in STEP KO neurons ( Fig.…”

Section: Blocking Step Substrates Prevents Ethanol Inhibition Of Nmdarmentioning

confidence: 81%

“…STEP C/S completely attenuated the effects of ethanol on NMDAR EPSCs, suggesting STEP activity was required for ethanol inhibition of NMDAR activity. STEP C/S binds to several STEP substrates and some of these substrates may be used by other cell-signaling pathways to regulate NMDAR activity (19,21). Therefore, we next tested the effects of ethanol on hippocampal synaptic NMDAR EPSCs in WT and STEP KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Six-to 9-wk-old SpragueDawley rats or STEP WT and KO mice were used in this study. STEP KO mice were generated by classic homologous recombination and back-crossed for 7 to 12 generations onto C57/B6 mice (21).…”

Section: Methodsmentioning

confidence: 99%

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Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

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

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Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr 1472 on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.whole-cell currents | null mutant mice A lcohol-induced memory deficits have been well documented in humans, as well as animal studies (1). Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying learning and memory in the hippocampus, as well as other brain regions (2), and is dependent upon NMDA receptor (NMDAR) activation (3). Acute ethanol application in adult rodents inhibits NMDAR channel activity (4, 5). Ethanol's inhibitory effect on NMDARs is widely thought to underlie both the blockade of LTP and the acute amnesic effects of ethanol. Moreover, recent work suggests that ethanol's effect on the NMDAR may play a role in the addictive nature of ethanol (6, 7).NMDARs in the hippocampus consist of mainly NR1/NR2A, NR1/NR2B, and NR1/NR2A/NR2B receptor-subunit complexes (8). Although NR1 subunits are required to form an active ion channel, incorporation of the various NR2 subunits regulate NMDAR channel activity by altering the channel kinetics and mediating the differential effects of pharmacological agents, including alcohol (9-11). It has previously been shown that activation of members of the Src-family of kinases (SFKs) enhances NMDAR currents (12). Previous studies have demonstrated a correlation between ethanol inhibition of NMDAR function and dephosphorylation of tyrosine residues on the NR2A and NR2B subunits (13). In particular, ethanol was found to reduce the phosphorylation of a site on the NR2B subunit Tyr 1472 that has been shown to regulate endocytosis and function of NMDARs (14,15). Inhibition of protein tyrosine phosphatase activity using a nonspecific inhibitor, bpV(phen), significantly reduced ethanol inhibition of NMDAR field excitatory postsynaptic potentials (fEPSPs), suggesting that ethanol may inhibit NMDARs via activation of a tyrosine phosphatase (13). FerraniKile et al. indepe...

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Section: Blocking Step Substrates Prevents Ethanol Inhibition Of Nmdarmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

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

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“…Findings in PTPN7 deficient mice, however, had suggested that KIM-containing PTP impact on MAP kinase cascades might be very subtle (Gronda et al, 2001). Furthermore, pharmacological inhibition (Paul et al, 2003;Valjent et al, 2005) and mouse knock-out studies also proved PTPN5 to be a physiological regulator of MAP kinase cascades (Venkitaramani et al, 2009). Indeed, also Ptprr knock-out mice displayed MAP kinase hyperphosphorylation in relevant tissues (Chirivi et al, 2007).…”

Section: Functionmentioning

confidence: 99%

PTPRR (protein tyrosine phosphatase, receptor type, R)

Erkens¹,

Kremer²,

Pulido³

et al. 2013

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…The affinity of the interaction between MAPK and the KIM dictates the selectivity of a MKP for a particular MAPK substrate (63). The KIM domain is also found in two tyrosine-specific PTPs, the striatalenriched PTP (STEP) and the hematopoietic PTP (HePTP), both of which are capable of dephosphorylating Erk (27,72). Again, in this instance, the KIM domain provides these tyrosine-specific PTPs with MAPK binding specificity and, hence, MAPK substrate selection.…”

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confidence: 99%

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

Soulsby

Bennett

2009

Physiology

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Intracellular signaling pathways that are mediated by tyrosyl phosphorylation are controlled through the balanced and opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The view that PTPs are equal contributing partners in the regulation of cellular tyrosyl phosphorylation continues to mature. However, there still remains the perception that PTPs play largely housekeeping roles. A growing body of evidence firmly dispels this perception, and it is evident that PTPs function with stringent signaling specificity, in concert with their PTK counterparts, to define specific biological outcomes. In this review, we will focus on illustrating that PTPs exhibit defined substrate specificity and subsequently regulate signaling pathways in a precise manner. The PTP SuperfamilyThe superfamily of PTPs is characterized by a consensus signature motif represented by HC(X) 5 R, which defines the active site of these enzymes. Two classes of PTPs can be defined (FIGURE 1). The first class is composed of classical PTPs that are defined by cysteine-based phosphotyrosine specificity, and the second class constitutes the dual-specificity phosphatases (DSPs). There are 37 classical human PTP genes that contain at least one PTP domain of ~280 amino acids. The DSPs are much larger in number, and there are 65 of these genes in the human genome. The classical PTP genes can be further subdivided into transmembrane receptor PTPs (RPTPs), or non-transmembrane PTPs, which localize to the cytoplasm (2, 4, 68). There are 12 RPTPs containing tandem PTP domains with the remainder containing a single PTP domain. The membrane-proximal PTP domain (D1) and membrane-distal PTP domain (D2) serve distinct roles. In the majority of cases, the D1 PTP domain comprises the active domain, whereas in most cases, but not all, the D2 domain serves a negative regulatory role. Although still quite controversial, evidence has been put forth to suggest that RPTPs are regulated through dimerization whereby RPTP activity is inhibited upon dimerization. However, there is also evidence against such a model of RPTP regulation, and further work in this particular area is warranted. Much like the RTKs, RPTPs utilize their diverse extracellular domains to transduce intracellular signals through binding to soluble ligands, but, in addition, RPTPs utilize their extracellular domains to mediate cell-cell and cell-matrix interactions (33,35,45,73). The nontransmembrane or cytoplasmic PTPs contain a single PTP domain, and their diversity is derived through noncatalytic regulatory domains that reside either at the NH 2 or COOH terminus of the PTP domain (2-3, 68). The noncatalytic domains are critical for exerting PTP substrate specificity and include one or more of the following features: 1) regulation of PTP activity, 2) directing subcellular localization, and 3) targeting PTP protein-protein interactions. Hence, the noncatalytic regions of the non-transmembrane PTPs offer a broad level of structural diversity, and together with the PTP...

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Knockout of STriatal enriched protein tyrosine phosphatase in mice results in increased ERK1/2 phosphorylation

Cited by 83 publications

References 26 publications

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

PTPRR (protein tyrosine phosphatase, receptor type, R)

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

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