1Mol. Membr. Biol. 2008 May 25: 353-62
TitleThe role of transmembrane AMPA receptor regulatory proteins (TARPs) in neurotransmission and receptor trafficking (Review).
AbstractAMPA receptors (AMPAR) mediate the majority of fast excitatory neurotransmission in the central nervous system (CNS). Transmembrane AMPAR regulatory proteins (TARPs) have been identified as a novel family of proteins which act as auxiliary subunits of AMPARs to modulate AMPAR trafficking and function. The trafficking of AMPARs to regulate the number of receptors at the synapse plays a key role in various forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). Expression of the prototypical TARP, stargazin/TARPgamma2, is ablated in the stargazer mutant mouse, an animal model of absence epilepsy and cerebellar ataxia. Studies on the stargazer mutant mouse have revealed that failure to express TARPgamma2 has widespread effects on the balance of expression of both excitatory (AMPAR) and inhibitory receptors (GABA(A) receptors, GABAR). The understanding of TARP function has implications for the future development of AMPAR potentiators, which have been shown to have therapeutic potential in both psychological and neurological disorders such as schizophrenia, depression and Parkinson's disease.
SCZ Keywordsschizophrenia
2Trends Neurosci. 2010 May 33: 241-8
TitleTARPs differentially decorate AMPA receptors to specify neuropharmacology.
AbstractTransmembrane AMPA receptor regulatory proteins (TARPs) are the first identified auxiliary subunits for a neurotransmitter-gated ion channel. Although initial studies found that stargazin, the prototypical TARP, principally chaperones AMPA receptors, subsequent research demonstrated that it also regulates AMPA receptor kinetics and synaptic waveforms. Recent studies have identified a diverse collection of TARP isoforms--types Ia, Ib II--that distinctly regulate AMPA receptor trafficking, gating and neuropharmacology. These TARP isoforms are heterogeneously expressed in specific neuronal populations and can differentially sculpt synaptic transmission and plasticity. Whole-genome analyses also link multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorder. TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders.
SCZ Keywordsschizophrenia
3ScientificWorldJournal 2011 -1 11: 454-7
TitlePharma TARP: a troubled asset relief program for novel, abandoned projects in the pharmaceutical industry.
AbstractWithin days of each other, Pfizer, Merck, and GlaxoSmithKline announced that they will focus on a few therapeutic areas only and abandon others entirely. Pfizer alone will close well over a hundred drug development projects that have reached two-thirds of the way to launch. The programs are deemed to be too risky and not lucrative enough for Big Pharma in the current climate. Society has a real need for the drugs that are no longer going to be developed for, among others, drug-resistant epilepsy, neuropathic and cancer pain, type-2 diabetes, obesity, and schizophrenia. The authors propose a radical response by the U.S. government and the National Institutes of Health to rescue these abandoned projects, and to continue selected programs for drug approval by the U.S. Food and Drug Administration and the European Medicines Agency. The investment required is small compared to the Troubled Asset Relief Program bank bail out, but the return on investment in financial terms and in satisfying societal needs makes this proposal attractive.
SCZ Keywordsschizophrenia
4Schizophr. Res. 2013 Jun 147: 32-8
TitleTransmembrane AMPA receptor regulatory protein (TARP) dysregulation in anterior cingulate cortex in schizophrenia.
AbstractThe glutamate hypothesis of schizophrenia proposes that abnormal glutamatergic neurotransmission occurs in this illness, and a major contribution may involve dysregulation of the AMPA subtype of ionotropic glutamate receptor (AMPAR). Transmembrane AMPAR regulatory proteins (TARPs) form direct associations with AMPARs to modulate the trafficking and biophysical functions of these receptors, and their dysregulation may alter the localization and activity of AMPARs, thus having a potential role in the pathophysiology of schizophrenia. We performed comparative quantitative real-time PCR and Western blot analysis to measure transcript (schizophrenia, N=25; comparison subjects, N=25) and protein (schizophrenia, N=36; comparison subjects, N=33) expression of TARPs (? subunits 1-8) in the anterior cingulate cortex (ACC) in schizophrenia and a comparison group. TARP expression was also measured in frontal cortex of rats chronically treated with haloperidol decanoate (28.5mg/kg every three weeks for nine months) to determine the effect of antipsychotic treatment on the expression of these molecules. We found decreased transcript expression of TARP ?-8 in schizophrenia. At the protein level, ?-3 and ?-5 were increased, while ?-4, ?-7 and ?-8 were decreased in schizophrenia. No changes in any of the molecules were noted in the frontal cortex of haloperidol-treated rats. TARPs are abnormally expressed at transcript and protein levels in ACC in schizophrenia, and these changes are likely due to the illness and not to the antipsychotic treatment. Alterations in the expression of TARPs may contribute to the pathophysiology of schizophrenia, and represent a potential mechanism of glutamatergic dysregulation in this illness.
SCZ Keywordsschizophrenia