NMDA Receptor - just starting - under construction

Last updated

Feb 23, 2024
Save as PDF
- Gluten and Celiac Disease
- RAS - just starting - under construction

$\newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} }$

$\newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}}$

$\newcommand{\id}{\mathrm{id}}$ $\newcommand{\Span}{\mathrm{span}}$

( \newcommand{\kernel}{\mathrm{null}\,}\) $\newcommand{\range}{\mathrm{range}\,}$

$\newcommand{\RealPart}{\mathrm{Re}}$ $\newcommand{\ImaginaryPart}{\mathrm{Im}}$

$\newcommand{\Argument}{\mathrm{Arg}}$ $\newcommand{\norm}[1]{\| #1 \|}$

$\newcommand{\inner}[2]{\langle #1, #2 \rangle}$

$\newcommand{\Span}{\mathrm{span}}$

$\newcommand{\id}{\mathrm{id}}$

$\newcommand{\Span}{\mathrm{span}}$

$\newcommand{\kernel}{\mathrm{null}\,}$

$\newcommand{\range}{\mathrm{range}\,}$

$\newcommand{\RealPart}{\mathrm{Re}}$

$\newcommand{\ImaginaryPart}{\mathrm{Im}}$

$\newcommand{\Argument}{\mathrm{Arg}}$

$\newcommand{\norm}[1]{\| #1 \|}$

$\newcommand{\inner}[2]{\langle #1, #2 \rangle}$

$\newcommand{\Span}{\mathrm{span}}$ $\newcommand{\AA}{\unicode[.8,0]{x212B}}$

$\newcommand{\vectorA}[1]{\vec{#1}} % arrow$

$\newcommand{\vectorAt}[1]{\vec{\text{#1}}} % arrow$

$\newcommand{\vectorB}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} }$

$\newcommand{\vectorC}[1]{\textbf{#1}}$

$\newcommand{\vectorD}[1]{\overrightarrow{#1}}$

$\newcommand{\vectorDt}[1]{\overrightarrow{\text{#1}}}$

$\newcommand{\vectE}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{\mathbf {#1}}}}$

$\newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} }$

$\newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}}$

$\newcommand{\avec}{\mathbf a}$

$\newcommand{\bvec}{\mathbf b}$

$\newcommand{\cvec}{\mathbf c}$

$\newcommand{\dvec}{\mathbf d}$

$\newcommand{\dtil}{\widetilde{\mathbf d}}$

$\newcommand{\evec}{\mathbf e}$

$\newcommand{\fvec}{\mathbf f}$

$\newcommand{\nvec}{\mathbf n}$

$\newcommand{\pvec}{\mathbf p}$

$\newcommand{\qvec}{\mathbf q}$

$\newcommand{\svec}{\mathbf s}$

$\newcommand{\tvec}{\mathbf t}$

$\newcommand{\uvec}{\mathbf u}$

$\newcommand{\vvec}{\mathbf v}$

$\newcommand{\wvec}{\mathbf w}$

$\newcommand{\xvec}{\mathbf x}$

$\newcommand{\yvec}{\mathbf y}$

$\newcommand{\zvec}{\mathbf z}$

$\newcommand{\rvec}{\mathbf r}$

$\newcommand{\mvec}{\mathbf m}$

$\newcommand{\zerovec}{\mathbf 0}$

$\newcommand{\onevec}{\mathbf 1}$

$\newcommand{\real}{\mathbb R}$

$\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}$

$\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}$

$\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}$

$\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}$

$\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}$

$\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}$

$\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}$

$\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}$

$\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}$

$\newcommand{\laspan}[1]{\text{Span}\{#1\}}$

$\newcommand{\bcal}{\cal B}$

$\newcommand{\ccal}{\cal C}$

$\newcommand{\scal}{\cal S}$

$\newcommand{\wcal}{\cal W}$

$\newcommand{\ecal}{\cal E}$

$\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}$

$\newcommand{\gray}[1]{\color{gray}{#1}}$

$\newcommand{\lgray}[1]{\color{lightgray}{#1}}$

$\newcommand{\rank}{\operatorname{rank}}$

$\newcommand{\row}{\text{Row}}$

$\newcommand{\col}{\text{Col}}$

$\renewcommand{\row}{\text{Row}}$

$\newcommand{\nul}{\text{Nul}}$

$\newcommand{\var}{\text{Var}}$

$\newcommand{\corr}{\text{corr}}$

$\newcommand{\len}[1]{\left|#1\right|}$

$\newcommand{\bbar}{\overline{\bvec}}$

$\newcommand{\bhat}{\widehat{\bvec}}$

$\newcommand{\bperp}{\bvec^\perp}$

$\newcommand{\xhat}{\widehat{\xvec}}$

$\newcommand{\vhat}{\widehat{\vvec}}$

$\newcommand{\uhat}{\widehat{\uvec}}$

$\newcommand{\what}{\widehat{\wvec}}$

$\newcommand{\Sighat}{\widehat{\Sigma}}$

$\newcommand{\lt}{<}$

$\newcommand{\gt}{>}$

$\newcommand{\amp}{&}$

$\definecolor{fillinmathshade}{gray}{0.9}$

Under Construction

Glutamatergic transmission has been implicated in the pathophysiology of PTSD, particularly in the effects of N-methyl-D-aspartate receptor (NMDAR) signaling on the synaptic plasticity underlying learning and memory [13]. NMDARs comprise two GluN1 subunits and two GluN2 (A-D) or GluN3 (A, B) subunits. In adult forebrain regions, GluN2A and GluN2B are the main subunits forming receptor complexes with GluN1 at excitatory synapses. GluN2B-containing NMDARs play a preferential role in inducing synaptic plasticity, which is critical for the extinction of fear memories [14, 15]. Systemic injection of GluN2B-specific NMDAR antagonists ((RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, ifenprodil) can impair the retention of fear extinction learning. GluN2B-containing NMDARs in both the amygdala and medial prefrontal cortex (mPFC) are also involved in reducing fear during extinction, whereas GluN2A-containing NMDARs play a greater role in the initial formation and/or stabilization of learned fear [15]. Rodent studies demonstrate that GluN2B subunit-containing NMDARs play pivotal roles in fear extinction learning.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263351/"tetrameric complexes mainly composed of NMDA receptor GluNR1 and GluNR2 subunits with the NR2 subunits modifying the activity of the receptor. "

N-methyl-d-aspartate (NMDA) receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore across the membrane bilayer.

NMDA receptors are Hebbian-like coincidence detectors, requiring the binding of glycine and glutamate to GluN1 and GluN2 subunits⁹, respectively, combined with membrane depolarization to relieve magnesium block ^10, 11. Activation of the receptor opens a cation-selective, calcium permeable channel, thus causing further depolarization of the cell membrane and influx of calcium ¹². NMDA receptors are obligatory heterotetrameric assemblies¹³^, 14, typically composed of two glycine-binding GluN1 subunits and two glutamate-binding GluN2A-D subunits, with the GluN1/GluN2A/GluN2B complex the predominate receptor at hippocampal synapses¹⁵. Glycine-and d-serine-binding GluN3 subunits are additional subunits, expressed throughout the nervous system but with roles less well defined in comparison to the GluN1/GluN2 assemblies. A hallmark of NMDA receptors, by contrast with AMPA and kainate receptors, is a wide spectrum of allosteric modulation, from nanomolar concentrations of zinc, to the small molecule ifenprodil, polyamines and protons¹⁶ and to voltage-dependent ion channel block by MK-801, ketamine and memantine¹⁷.

The coordinates and structure factors for the structure have been deposited in the Protein Data Bank under accession code 4TLL and 4TLM for Structure 1 and Structure 2, respectively.

These receptors have two GluN1 subunits and two GluN2 (A-D) or GluN3 (A, B) subunits. In the forebrain, GluN2A and B form complex with GluN1 at synapses, with the B subunit playing a role in synaptic plasticity. Synaptic plasticity is necessary to remove "hard-wired" fear circuits. A goal of PTSD therapies is the extinction of the previously acquired feared memories through learning. Learning, and more specifically extinction, requires synaptic plasticity.

If one goal of PTSD treatment is the extinction of fear memories, then drugs that target GluN2B are potentially useful. Antagonist (such asd ifenprodil) of GluN2B seem to decrease the ability to extinguish fear retention memories. In other words, the learning and synaptic plasticity need to attenuate the fear memories are inhibited by the antagonist. GluN2B in the NMDAR receptors in the amygdala and medial prefrontal cortex appear to be involved in reducing feat during extinction. IN contact, GluN2A seem to be an important role in forming and stabilizing the learned fear response.

"Glutamatergic transmission has been implicated in the pathophysiology of PTSD, particularly in the effects of N-methyl-D-aspartate receptor (NMDAR) signaling on the synaptic plasticity underlying learning and memory [13]. NMDARs comprise two GluN1 subunits and two GluN2 (A-D) or GluN3 (A, B) subunits. In adult forebrain regions, GluN2A and GluN2B are the main subunits forming receptor complexes with GluN1 at excitatory synapses. GluN2B-containing NMDARs play a preferential role in inducing synaptic plasticity, which is critical for the extinction of fear memories [14, 15]. Systemic injection of GluN2B-specific NMDAR antagonists ((RS)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, ifenprodil) can impair the retention of fear extinction learning. GluN2B-containing NMDARs in both the amygdala and medial prefrontal cortex (mPFC) are also involved in reducing fear during extinction, whereas GluN2A-containing NMDARs play a greater role in the initial formation and/or stabilization of learned fear [15]. Rodent studies demonstrate that GluN2B subunit-containing NMDARs play pivotal roles in fear extinction learning."

Describe how the NMDA receptor functions, and how it implements the Hebbian model of learning at the synaptic level.

http://charlesfrye.github.io/Foundat...roscience//29/

https://www.pnas.org/doi/full/10.1073/pnas.95.12.7145

https://pubmed.ncbi.nlm.nih.gov/15888440/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263351/

CC *** https://www.nature.com/articles/s41380-022-01498-7