Perspective: One-Cell and Cleavage-Stage Mouse Embryos Thrive in Hyperosmotic Oviductal Fluid Through Expression of a Glycine Neurotransmitter Transporter and a Glycine-Gated Chloride Channel: Clinical and Transgenerational Implications

The osmolality of mouse oviductal fluid ranges from about 300 mOsmol/kg in the ampulla 0–3 h post coitus (h p.c.) to more than 350 mOsmol/kg in the isthmus 34–36 h p.c. Thus, it has been surprising to find that development of one-cell and cleavage-stage mouse embryos arrests in vitro in media exceeding 300 mOsmol/kg, and they develop best in unphysiological, hypotonic media. The glycine concentration in oviductal fluid can, however, rescue development in hypertonic media, so physiological conditions in vivo and in vitro likely work together to foster embryo well-being. Glycine acts on one-cell and cleavage-stage mouse embryos through the glycine-gated chloride channel, GLRA4, and uptake via the glycine neurotransmitter transporter, GLYT1. Since these processes lead to further signaling in neurons, the presence and function of such signaling in preimplantation embryos also should be investigated. The more we know about the interactions of physiological processes and conditions in vivo, the better we would be able to reproduce them in vitro. Such improvements in assisted reproductive technology (ART) could improve patient outcomes for IVF and potentially help prevent unwanted developmental abnormalities in early embryos, which might include undesirable epigenetic DNA and histone modifications. These epigenetic modifications may lead to transgenerational adult disorders such as metabolic syndrome and related conditions.

Fatal intoxication with PMMA – a novel designer analogue of amphetamine

Introduction: New designer drugs of the amphetamine class like 4-methoxyamphetamine (PMA) and 4-methoxymethamphetamine (PMMA) elicit psychoactive effects in the central nervous system (CNS) by enhancing monoaminergic neurotransmission. These substances are substrates for neurotransmitter transporter proteins, and after binding with them they penetrate inside the cells. PMA and PMMA also reverse the transport of endogenic neurotransmitters and stimulate their increased release into the synaptic gap. PMMA has a weaker psychostimulating effect and a stronger hallucinogenic effect than PMA.Materials and methods: The article presents the case of fatal PMMA intoxication in a 28-year-old man. The post-mortem forensic toxicological analysis of collected blood samples was performed using the LC/MS/MS technique. The analysis detected 213 ng/mL of amphetamine, 270 ng/mL of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), and 4585 ng/mL of PMMA.Results: The cause of death was acute multiple organ failure resulting from heavy intoxication with psychoactive substances, particularly with PMMA.

SLC6 neurotransmitter transporter family (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Members of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [29, 22, 70] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [99]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+-dependent amino acid transporter from Aquiflex aeolicus [126] and in several other transporter families structurally related to LeuT [45].