Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock.

NMDA receptor (NMDAR)-mediated currents depend on membrane depolarization to relieve powerful voltage-dependent NMDAR channel block by external magnesium (Mg(o)(2+)). Mg(o)(2+) unblock from native NMDARs exhibits a fast component that is consistent with rapid Mg(o)(2+) -unbinding kinetics and also a slower, millisecond time scale component (slow Mg(o)(2+) unblock). In recombinant NMDARs, slow Mg(o)(2+) unblock is prominent in GluN1/2A (an NMDAR subtype composed of GluN1 and GluN2A subunits) and GluN1/2B receptors, with slower kinetics observed for GluN1/2B receptors, but absent from GluN1/2C and GluN1/2D receptors. Slow Mg(o)(2+) unblock from GluN1/2B receptors results from inherent voltage-dependent gating, which increases channel open probability with depolarization. Here we examine the mechanisms responsible for NMDAR subtype dependence of slow Mg(o)(2+) unblock. We demonstrate that slow Mg(o)(2+) unblock from GluN1/2A receptors, like GluN1/2B receptors, results from inherent voltage-dependent gating. Surprisingly, GluN1/2A and GluN1/2B receptors exhibited equal inherent voltage dependence; faster Mg(o)(2+) unblock from GluN1/2A receptors can be explained by voltage-independent differences in gating kinetics. To investigate the absence of slow Mg(o)(2+) unblock in GluN1/2C and GluN1/2D receptors, we examined the GluN2 S/L site, a site responsible for several NMDAR subtype-dependent channel properties. Mutating the GluN2 S/L site of GluN2A subunits from serine (found in GluN2A and GluN2B subunits) to leucine (found in GluN2C and GluN2D) greatly diminished both voltage-dependent gating and slow Mg(o)(2+) unblock. Therefore, the residue at the GluN2 S/L site governs the expression of both slow Mg(o)(2+) unblock and inherent voltage dependence.

HSV delivery of a ligand-regulated endogenous ion channel gene to sensory neurons results in pain control following channel activation.

Persistent pain remains a tremendous health problem due to both its prevalence and dearth of effective therapeutic interventions. To maximize pain relief while minimizing side effects, current gene therapy-based approaches have mostly exploited the expression of pain inhibitory products or interfered with pronociceptive ion channels. These methods do not enable control over the timing or duration of analgesia, nor titration to analgesic efficacy. Here, we describe a gene therapy strategy that potentially overcomes these limitations by providing exquisite control over therapy with efficacy in clinically relevant models of inflammatory pain. We utilize a herpes simplex viral (HSV) vector (vHGlyRα1) to express a ligand-regulated chloride ion channel, the glycine receptor (GlyR) in targeted sensory afferents; the subsequent exogenous addition of glycine provides the means for temporal and spatial control of afferent activity, and therefore pain. Use of an endogenous inhibitory receptor not normally present on sensory neurons both minimizes immunogenicity and maximizes therapeutic selectivity.

Lurasidone for Adolescents With Complex Mental Disorders: A Case Series.

OBJECTIVES: Lurasidone is a new second generation (atypical) antipsychotic agent with unique receptor affinity and side-effect profiles, but limited literature is available on its use in adolescent populations. Contrasting with research treatment trials which typically recruit patients by stringent selection criteria, this case series examined the effects and tolerability of using lurasidone in adolescents within real-life clinical settings in treating complex cases who had not responded to other therapy options. METHODS: We conducted a retrospective case-note audit of 6 adolescents aged 14 to 17 years old attending community child and adolescent mental health services (CAMHS) who were prescribed lurasidone. RESULTS: Lurasidone had been prescribed for a range of "hard-to-manage" conditions with complex comorbidities, in adolescents in relation to specific use of lurasidone on the basis of clinical and pharmacological indications after exhausting more conventional treatment options. Case-note review suggested response to lurasidone was clinically positive in 3 cases, equivocal/marginal in 2 cases, and ineffective in 1 case. There were no cases of poor tolerance or adverse effects. Notably, positive responses for depressive and irritable mood symptoms were specifically recorded by prescribing clinicians, indicative of benefits on symptom improvement. No lurasidone attributed weight gain, galactorrhoea, metabolic abnormalities, sexual dysfunction or intolerance were reported. Pro-cognitive effects were not detected; but our findings were constrained by the non-systematic and incomplete information ascertainment, typical in retrospective case-note review. CONCLUSION: This case series provides preliminary data supporting lurasidone's potential use in adolescents of complex clinical needs (but without a clinical diagnosis of bipolar disorder) within real-life clinical settings. Lurasidone appears to show a weight-sparing effect, in addition to improving mood symptoms in some cases. Lurasidone deserves further study for its use in the adolescent population (outside the remit of FDA) given its potential more favorable risk-benefit profile in young people. The favorable tolerability appear to be borne out by the pharmacodynamic predictions in our complex patients who would be excluded in formal clinical trial studies.

Voltage-dependent gating of NR1/2B NMDA receptors.

Ligand-gated ion channels are activated by agonist binding, but may also be modulated by membrane voltage. N-Methyl-d-aspartate receptors (NMDARs) exhibit especially strong voltage dependence due to channel block by external Mg(2+) (Mg(o)(2+)). Here we demonstrate that activity of NMDARs composed of NR1 and NR2B subunits (NR1/2B receptors) is enhanced by depolarization even in 0 Mg(o)(2+), causing slow current relaxations in response to rapid voltage changes. We present a kinetic model of receptor activation that incorporates voltage-dependent gating-associated NR2B subunit conformational changes. The model accurately reproduces current relaxations during depolarizations and subsequent repolarizations in 0 Mg(o)(2+). Model simulations in physiological Mg(o)(2+) concentrations show that voltage-dependent receptor gating also underlies the slow component of Mg(o)(2+) unblock, a phenomenon that previously was shown to influence Mg(o)(2+) unblock kinetics during dendritic spikes. We propose that voltage-dependent gating of NR1/2B receptors confers enhanced voltage and time dependence on NMDAR-mediated signalling.

NMDA receptor NR2 subunit dependence of the slow component of magnesium unblock.

NMDA receptor activity is important for many physiological functions, including synapse formation and alterations in synaptic strength. NMDA receptors are composed most commonly of NR1 and NR2 subunits. There are four NR2 subunits (NR2A-NR2D). NR2 subunit expression varies across both brain regions and developmental stages. The identity of the NR2 subunit within a functional NMDA receptor helps to determine many pharmacological and biophysical receptor properties, including strength of block by external Mg2+ (Mg(o)2+). Mg(o)2+ block confers strong voltage dependence to NMDA receptor-mediated responses and is critically important for many of the functions that the NMDA receptor plays within the CNS. Here we describe the NR2 subunit dependence of the kinetics of Mg(o)2+ unblock after rapid depolarizations. We find that Mg(o)2+ unblocks from NR1/2A and NR1/2B receptors with a prominent slow component similar to that previously described in native hippocampal and cortical NMDA receptors. Strikingly, this slow component of Mg(o)2+ unblock is completely absent from NR1/2C and NR1/2D receptors. Thus currents from NR1/2C and NR1/2D receptors respond more rapidly to fast depolarizations than currents from NR1/2A and NR1/2B receptors. In addition, the slow component of Mg(o)2+ unblock from NR1/2B receptors is consistently slower than from NR1/2A receptors. This makes rapid depolarizations, such as action potential waveforms, more efficacious at stimulating Mg(o)2+ unblock from NR1/2A than from NR1/2B receptors. These NR2 subunit differences in the kinetics of Mg(o)2+ unblock are likely to help determine the contribution of each NMDA receptor subtype to current flow during synaptic activity.

Amantadine inhibits NMDA receptors by accelerating channel closure during channel block.

The channel of NMDA receptors is blocked by a wide variety of drugs. NMDA receptor channel blockers include drugs of abuse that induce psychotic behavior, such as phencyclidine, and drugs with wide therapeutic utility, such as amantadine and memantine. We describe here the molecular mechanism of amantadine inhibition. In contrast to most other described channel-blocking molecules, amantadine causes the channel gate of NMDA receptors to close more quickly. Our results confirm that amantadine binding inhibits current flow through NMDA receptor channels but show that its main inhibitory action at pharmaceutically relevant concentrations results from stabilization of closed states of the channel. The surprising variation in the clinical utility of NMDA channel blockers may in part derive from their diverse effects on channel gating.

What neural correlates underlie successful encoding and retrieval? A functional magnetic resonance imaging study using a divided attention paradigm.

If attention is divided during learning, memory suffers. Nevertheless, individuals can learn information with divided attention. This event-related functional magnetic resonance imaging (fMRI) study (n = 17) investigated what neural processes support (1) learning with divided attention and (2) retrieval of information learned with divided attention. Participants encoded words (Is the word abstract or concrete?) while performing an auditory discrimination task (press a button whenever an auditory pattern changes). The auditory task was easy or hard, depending on the similarity of the patterns. A behavioral study indicated that detailed ("recollective") information was more likely to be present for words encoded with the easy versus the hard concurrent task. Words encoded with the hard versus the easy concurrent task, in contrast, were more likely to rely on less detailed ("familiarity"-based) information. fMRI revealed encoding-related activation in the left prefrontal cortex (PFC) and left hippocampus that was linked to successful memory formation only for items encoded with the easy task. In contrast, activation in the right PFC and left parahippocampal gyrus was linked to successful memory for all items. Thus, successful encoding with the hard concurrent task was supported by a subset of the regions recruited for successful encoding with the easy task. The neural processes recruited for successful retrieval also depended on the encoding condition: The left PFC was disproportionately recruited for retrieval of items encoded with the easy task, whereas the right PFC was disproportionately recruited for retrieval of items encoded with the hard task. These findings may reflect left-sided specialization for recollective memories and right-sided specialization for familiarity-based traces.