PubMed Health⌕ Search

Biomedical subjects

Lorraine V Kalia

Publications and source records attributed to Lorraine V Kalia.

9 recordsLinked to original sources
PubMed2006

PSD-95 is a negative regulator of the tyrosine kinase Src in the NMDA receptor complex.

The tyrosine kinase Src upregulates the activity of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) and tyrosine phosphorylation of this receptor is critical for induction of NMDAR-dependent plasticity of synaptic transmission. A binding partner for Src within the NMDAR complex is the protein PSD-95. Here we demonstrate an interaction of PSD-95 with Src that does not require the well-characterized domains of PSD-95. Rather, we show binding to Src through a 12-amino-acid sequence in the N-terminal region of PSD-95, a region not previously known to participate in protein-protein interactions. This region interacts directly with the Src SH2 domain. Contrary to typical SH2 domain binding, the PSD-95-Src SH2 domain interaction is phosphotyrosine-independent. Binding of the Src-interacting region of PSD-95 inhibits Src kinase activity and reduces NMDAR phosphorylation. Intracellularly administering a peptide matching the Src SH2 domain-interacting region of PSD-95 depresses NMDAR currents in cultured neurons and inhibits induction of long-term potentiation in hippocampus. Thus, the PSD-95-Src SH2 domain interaction suppresses Src-mediated NMDAR upregulation, a finding that may be of broad importance for synaptic transmission and plasticity.

Animals↗
PubMed2005

Severity of chronic pain and its relationship to quality of life in multiple sclerosis.

INTRODUCTION: This study used reliable and validated instruments to compare pain severity in multiple sclerosis (MS) to that in other chronic painful conditions, and to examine relationships between chronic pain in MS and health-related quality of life (HRQOL). METHODS: Ninety-nine MS patients completed a self-administered survey comprised of the Medical Outcomes 36-Item Short-Form Health Survey, the Short-Form McGill Pain Questionnaire, and the Hospital Anxiety and Depression Scale. RESULTS: Pain severity was not different between MS patients with pain and rheumatoid arthritis (P = 0.77) or osteoarthritis (P = 0.98) patients. Chronic pain in MS was less often neurogenic than non-neurogenic, although severity of neurogenic pain was greater than that of non-neurogenic pain (P = 0.048). Chronic pain in MS was found to have no significant relationship to age, disease duration or disease course. Instead, we found that pain was correlated with aspects of HRQOL, particularly mental health (r = 0.44, P < 0.0001) versus physical functioning (r = 0.19, P > 0.05). Chronic pain was significantly related to anxiety and depression for females but not for males with MS. CONCLUSIONS: Chronic pain in MS is as severe as pain in arthritic conditions and is associated with reduced HRQOL. Thus, pain can be a significant symptom for MS patients and the need for treatment may be underestimated.

Adult↗
PubMed2004

Src in synaptic transmission and plasticity.

In the central nervous system (CNS), Src and other Src family kinases are widely expressed and are abundant in neurons. Src has been implicated in proliferation and differentiation during the development of the CNS. But Src is highly expressed in fully differentiated neurons in the developed CNS, implying additional functions of this kinase. Over the past decade, a large body of evidence has accumulated showing that a main function of Src is to upregulate the activity of N-methyl-D-aspartate (NMDA) receptors and other ion channels. NMDA receptors (NMDARs) are a principal subtype of glutamate receptors, which mediate fast excitatory transmission at most central synapses. In this review, we focus on Src as a regulator of NMDARs and on the role of Src in NMDAR-dependent synaptic plasticity. We also describe recent studies that give insights into the regulation of Src itself at glutamatergic synapses. By upregulating the function of NMDARs, Src gates the production of NMDAR-dependent synaptic potentiation and plasticity. Thus, Src may be critical for processes underlying physiological plasticity, including learning and memory, and pathological plasticity, such as pain and epilepsy.

Animals↗
PubMed2003

Differential frequency dependence of P2Y1- and P2Y2- mediated Ca 2+ signaling in astrocytes.

ATP is a key extracellular messenger that mediates the propagation of Ca 2+ waves in astrocyte networks in various regions of the CNS. ATP-mediated Ca 2+ signals play critical roles in astrocyte proliferation and differentiation and in modulating neuronal activity. The actions of ATP on astrocytes are via two distinct subtypes of P2Y purinoceptors, P2Y1 and P2Y2 receptors (P2Y1Rs and P2Y2Rs), G-protein coupled receptors that stimulate mobilization of intracellular Ca 2+ ([Ca 2+]i) via the phospholipase Cbeta-IP3 pathway. We report here that P2Y1R-mediated and P2Y2R-mediated Ca 2+ responses differentially show two forms of activity-dependent negative feedback. First, Ca 2+ responses mediated by either receptor exhibit slow depression that is independent of stimulation frequency. Second, responses mediated by P2Y1Rs, but not those mediated by P2Y2Rs, show rapid oscillations after high-frequency stimulation. We demonstrate that the oscillations are mediated by recruiting negative feedback by protein kinase C, and we map the site responsible for the effect of protein kinase C to Thr339 in the C terminus of P2Y1R. We propose that frequency-dependent changes in ATP-mediated Ca 2+ signaling pathways may modulate astrocyte function and astrocyte-neuron signaling in the CNS.

Adenosine Diphosphate↗
PubMed2003

Glycine binding primes NMDA receptor internalization.

NMDA (N-methyl-d-aspartate) receptors (NMDARs) are a principal subtype of excitatory ligand-gated ion channel with prominent roles in physiological and disease processes in the central nervous system. Recognition that glycine potentiates NMDAR-mediated currents as well as being a requisite co-agonist of the NMDAR subtype of 'glutamate' receptor profoundly changed our understanding of chemical synaptic communication in the central nervous system. The binding of both glycine and glutamate is necessary to cause opening of the NMDAR conductance pore. Although binding of either agonist alone is insufficient to cause current flow through the channel, we report here that stimulation of the glycine site initiates signalling through the NMDAR complex, priming the receptors for clathrin-dependent endocytosis. Glycine binding alone does not cause the receptor to be endocytosed; this requires both glycine and glutamate site activation of NMDARs. The priming effect of glycine is mimicked by the NMDAR glycine site agonist d-serine, and is blocked by competitive glycine site antagonists. Synaptic as well as extrasynaptic NMDARs are primed for internalization by glycine site stimulation. Our results demonstrate transmembrane signal transduction through activating the glycine site of NMDARs, and elucidate a model for modulating cell-cell communication in the central nervous system.

Adaptor Protein Complex beta Subunits↗
PubMed2003

Interactions between Src family protein tyrosine kinases and PSD-95.

Five members of the Src family of non-receptor protein tyrosine kinases--Lck, Lyn, Fyn, Src, and Yes--are known to be expressed in the central nervous system. Src and Fyn have been shown to play important roles in synaptic transmission and plasticity at excitatory synapses. Here we investigate the subcellular distribution and potential binding partners of Src family protein tyrosine kinases in brain, focusing on the lesser studied kinases Lck, Lyn, and Yes. We find that Lck, Lyn, and Yes are localized to the postsynaptic density (PSD), the primary structural component of excitatory synapses. Lyn and Yes, as well as Src, but not Lck physically associate with the prominent PSD scaffolding protein PSD-95 in co-immunoprecipitation experiments. Further, we demonstrate that PSD-95 GST fusion proteins bind directly to purified recombinant Lyn, Src, and Yes in vitro. In addition, we show that PSD-95 is unique among PSD-95 family members in that the other members, PSD-93, SAP97, and SAP102, do not physically associate with Lyn, Src, or Yes. Together our results suggest that PSD-95 may be important for localizing and/or regulating multiple Src protein tyrosine kinases at the NMDA receptor multiprotein complex.

Animals↗
PubMed2002

Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation.

The functional roles of protein tyrosine phosphatases (PTPs) in the developed CNS have been enigmatic. Here we show that striatal enriched tyrosine phosphatase (STEP) is a component of the N-methyl-D-aspartate receptor (NMDAR) complex. Functionally, exogenous STEP depressed NMDAR single-channel activity in excised membrane patches. STEP also depressed NMDAR-mediated synaptic currents whereas inhibiting endogenous STEP enhanced these currents. In hippocampal slices, administering STEP into CA1 neurons did not affect basal glutamatergic transmission evoked by Schaffer collateral stimulation but prevented tetanus-induced long-term potentiation (LTP). Conversely, inhibiting STEP in CA1 neurons enhanced transmission and occluded LTP induction through an NMDAR-, Src-, and Ca(2+)-dependent mechanism. Thus, STEP acts as a tonic brake on synaptic transmission by opposing Src-dependent upregulation of NMDARs.

Animals↗