PausePassage 4 (Questions 25–30)The N-methyl-D-aspartate receptor (NMDAR) is a 500 kDa heterotetrameric protein that is one of the main mediators of excitatory signaling between neurons in the mammalian brain.  Arranged as a dimer of identical heterodimers, one subunit in each dimer binds glutamate molecules and the other binds glycine molecules that are released by the pre-synaptic neuron.  Upon binding to both of these agonists, the NMDAR subsequently allows for the passage of sodium and potassium ions across the postsynaptic membrane by passing them through its transmembrane domain.  However, in the overly prolonged presence of agonists, the receptor undergoes a process known as desensitization, wherein it adopts a new form that does not allow for the passage of ions despite continued agonist binding.In addition to the co-agonists that activate the NMDAR, other molecules can modulate NMDAR activity when applied concurrently.  For example, extracellular application of a polyamine molecule called spermine results in its binding to the amino-terminal domain of the NMDAR, affecting the current passing through the receptor as shown in Figure 1.Figure 1  Whole-cell patch-clamp electrophysiological currents in Chinese Hamster Ovary (CHO) cells transfected with NMDAR.  Saturating glycine is continuously applied.  Saturating glutamate and spermine were applied while indicated by their respective arrows.Researchers studied the effect of spermine binding on the NMDAR protein conformation using spectroscopic methods.  These measurements showed that the amino-terminal domain changed from a partially open clamshell-like conformation to a fully open clamshell-like conformation upon spermine binding (Figure 2).Figure 2  Cartoon structure of NMDAR with agonists and with and without spermine.  (A) The amino-terminal and agonist-binding domains are extracellular, and the carboxy-terminal domain is intracellular.  The 12-transmembrane helix transmembrane domain lies in between.  (B) A close-up of the conformational changes seen in the amino-terminal domain upon spermine binding.Sirrieh RE, MacLean DM, Jayaraman V. Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine. J Biol Chem. 2015 May 15;290(20):12812-20. doi: 10.1074/jbc.M115.649723. Epub 2015 Mar 31. PMID: 25829490; PMCID: PMC4432297. Question 26Under saturating agonist conditions, which functional state describes the NMDAR conformation that has the lowest Gibbs free energy?A.Bound to agonists and impermeant to ionsB.Bound to agonists and permeant to ionsC.Unbound to agonists and permeant to ionsD.Unbound to agonists and impermeant to ions

The N-methyl-D-aspartate receptor (NMDAR) is a 500 kDa heterotetrameric protein that is one of the main mediators of excitatory signaling between neurons in the mammalian brain.  Arranged as a dimer of identical heterodimers, one subunit in each dimer binds glutamate molecules and the other binds glycine molecules that are released by the pre-synaptic neuron.  Upon binding to both of these agonists, the NMDAR subsequently allows for the passage of sodium and potassium ions across the postsynaptic membrane by passing them through its transmembrane domain.  However, in the overly prolonged presence of agonists, the receptor undergoes a process known as desensitization, wherein it adopts a new form that does not allow for the passage of ions despite continued agonist binding.In addition to the co-agonists that activate the NMDAR, other molecules can modulate NMDAR activity when applied concurrently.  For example, extracellular application of a polyamine molecule called spermine results in its binding to the amino-terminal domain of the NMDAR, affecting the current passing through the receptor as shown in Figure 1.Figure 1  Whole-cell patch-clamp electrophysiological currents in Chinese Hamster Ovary (CHO) cells transfected with NMDAR.  Saturating glycine is continuously applied.  Saturating glutamate and spermine were applied while indicated by their respective arrows.Researchers studied the effect of spermine binding on the NMDAR protein conformation using spectroscopic methods.  These measurements showed that the amino-terminal domain changed from a partially open clamshell-like conformation to a fully open clamshell-like conformation upon spermine binding (Figure 2).Figure 2  Cartoon structure of NMDAR with agonists and with and without spermine.  (A) The amino-terminal and agonist-binding domains are extracellular, and the carboxy-terminal domain is intracellular.  The 12-transmembrane helix transmembrane domain lies in between.  (B) A close-up of the conformational changes seen in the amino-terminal domain upon spermine binding.Sirrieh RE, MacLean DM, Jayaraman V. Subtype-dependent N-methyl-D-aspartate receptor amino-terminal domain conformations and modulation by spermine. J Biol Chem. 2015 May 15;290(20):12812-20. doi: 10.1074/jbc.M115.649723. Epub 2015 Mar 31. PMID: 25829490; PMCID: PMC4432297. Question 28Based on the passage, what is the best description of the effect of spermine binding to the NMDAR?A.Spermine is a co-agonist, necessary for NMDAR function.B.Spermine binding changes the equilibrium membrane potential for sodium.C.Spermine increases the Hill coefficient to above 1.D.Spermine increases the rate of sodium transfer.

PCP and ketamine act on the postsynaptic cell by Group of answer choicesblocking the NMDA receptor at the glutamate site.stimulating the receptor where NMDA normally binds.acting as a competitive antagonist at the NMDA receptor.acting as an uncompetitive antagonist at the NMDA receptor.

An NMDA receptor channel is blocked by magnesium unlessGroup of answer choicescalcium binds to autoreceptors on the presynaptic neuronglutamate binds to all the receptors on the dendritethe postsynaptic neuron is already hyperpolarizedCA3 field pyramidal cell is repeatedly stimulatedthe postsynaptic membrane is already depolarized

A secondary consequence of NMDA receptor antagonism is _______ presynaptic glutamate release, which may result from _______ of receptors on inhibitory GABAergic interneurons that innervate the cortical neurons. Group of answer choicesdecreased; blockadedecreased; openingincreased; blockadeincreased; opening

NMDA receptor agonists depolarise the lamprey spinal neurons by:Group of answer choicesclosing all calcium channelsopening channels permeable to sodium and calcium ionsopening chloride channelsopening dopamine channelsclosing slow serotonin channels