AMPA receptors form a major subdivision of the glutamate receptor family that mediates excitatory synaptic transmission in the brain. Currents through AMPA receptors can be up- or down-regulated by compounds that allosterically modulate receptor kinetics through binding sites distinct from that for glutamate. One of those modulators is the benzothiadiazide IDRA-21 which has been reported to enhance synaptic transmission and be effective in behavioral tests, but typically requires threshold concentrations of at least 100 microM to be active in vitro. In this study, new benzothiadiazides were developed with IDRA-21 as lead compound and examined for their potency in modulating AMPA receptor kinetics. A significant increase in drug affinity was obtained by alkyl substitution at the 5'-position of IDRA-21; substitutions at other positions of the benzothiadiazide core generally did not yield a further gain in affinity and in some cases abolished drug binding. The 5'-ethyl derivative exhibited an EC(50) value in the order of 22 microM which represents about a 30-fold gain in affinity over that of IDRA-21. The EC(50) value is comparable to that of cyclothiazide, the most potent benzothiadiazide drug, but the effects on AMPA receptors differed substantially between these two compounds in that the 5'-ethyl derivative of IDRA-21 greatly increased the binding affinity for receptor agonists whereas cyclothiazide is known to reduce agonist binding. The structure--activity relationships reported here thus offer to provide new insights how receptor kinetics is linked to particular aspects of receptor--drug interactions.
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http://dx.doi.org/10.1016/s0968-0896(01)00405-9 | DOI Listing |
Nature
January 2025
Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA.
The zeta inhibitory peptide (ZIP) interferes with memory maintenance and long-term potentiation (LTP) when administered to mice. However, mice lacking its putative target, protein kinase PKMζ, exhibit normal learning and memory as well as LTP, making the mechanism of ZIP unclear. Here we show that ZIP disrupts LTP by removing surface AMPA receptors through its cationic charge alone.
View Article and Find Full Text PDFNat Commun
January 2025
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. With cryo-electron microscopy (cryo-EM) we reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å, which points to structural diversity among TARPs.
View Article and Find Full Text PDFJ Neurosci
January 2025
Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University School of Medicine, Morgantown, WV, USA.
Synaptically released zinc is a neuronal signaling system that arises from the actions of the presynaptic vesicular zinc transporter protein ZnT3. Mechanisms that regulate the actions of zinc at synapses are of great importance for many aspects of synaptic signaling in the brain. Here, we identify the astrocytic zinc transporter protein ZIP12 as a candidate mechanism that contributes to zinc clearance at cortical synapses.
View Article and Find Full Text PDFCell Rep
January 2025
Department of Cell Biology and Anatomy, LSUHSC, New Orleans, LA 70112, USA; Southeast Louisiana VA Healthcare System, New Orleans, LA 70119, USA. Electronic address:
Stress can alter behavior and contributes to psychiatric disorders by regulating the expression of the GluA2 AMPA receptor subunit. We have previously shown in mice that exposure to predator odor stress elevates GluA2 transcription in cerebellar molecular layer interneurons (MLIs), and MLI activity is required for fear memory consolidation. Here, we identified the critical involvement of adenylyl cyclase 5, in both the stress-induced increase in GluA2 in MLIs and the enhancement of fear memory.
View Article and Find Full Text PDFJ Neurosci
January 2025
Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA, Amsterdam, The Netherlands.
The detrimental effects of oligomeric amyloid-β (Aβ) on synapses are considered the leading cause for cognitive deficits in Alzheimer's disease. However, through which mechanism Aβ oligomers impair synaptic structure and function remains unknown. Here, we used electrophysiology and AMPA-receptor (AMPAR) imaging on mice and rat neurons to demonstrate that GluA3 expression in neurons lacking GluA3 is sufficient to re-sensitize their synapses to the damaging effects of Aβ, indicating that GluA3-containing AMPARs at synapses are necessary and sufficient for Aβ to induce synaptic deficits.
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