SummaryHeterozygous mutations in proline-rich transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders, including epilepsy, kinesigenic dyskinesia, and migraine. Most of the mutations lead to impaired PRRT2 expression, suggesting that loss of PRRT2 function may contribute to pathogenesis. We show that PRRT2 is enriched in presynaptic terminals and that its silencing decreases the number of synapses and increases the number of docked synaptic vesicles at rest. PRRT2-silenced neurons exhibit a severe impairment of synchronous release, attributable to a sharp decrease in release probability and Ca2+ sensitivity and associated with a marked increase of the asynchronous/synchronous release ratio. PRRT2 interacts with the synaptic proteins SNAP-25 and synaptotagmin 1/2. The results indicate that PRRT2 is intimately connected with the Ca2+-sensing machinery and that it plays an important role in the final steps of neurotransmitter release.

The 118A>G single nucleotide polymorphism (SNP) in the μ-opioid receptor (OPRM1) gene has been the most described variant in pharmacogenetic studies regarding opioid drugs. Despite evidence for an altered biological function encoded by this variant, this knowledge is not yet utilized clinically. The aim of the present review was to collect and discuss the available information on the 118A>G SNP in the OPRM1 gene, at the molecular level and in its clinical manifestations. In vitro biochemical and molecular assays have shown that the variant receptor has higher binding affinity for β-endorphins, that it has altered signal transduction cascade, and that it has a lower expression compared with wild-type OPRM1. Studies using animal models for 118A>G have revealed a double effect of the variant receptor, with an apparent gain of function with respect to the response to endogenous opioids but a loss of function with exogenous administered opioid drugs. Although patients with this variant have shown a lower pain threshold and a higher drug consumption in order to achieve the analgesic effect, clinical experiences have demonstrated that patients carrying the variant allele are not affected by the increased opioid consumption in terms of side effects.

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BackgroundWe previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA.Methodology/FindingsWe used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA.Conclusions/SignificanceThe results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.