[Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: a new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia]. / Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3: Ein neuer molekularer Mechanismus der Atmungskontrolle zur Kompensation opioidinduzierter Atemdepression ohne Verlust der Analgesie.

To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor α3. The specific activation of serotonin receptor type 1A (5-HTR(1A)), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type α3 (GlyRα3). This 5-HTR(1A)-GlyRα3 signal pathway is independent of the µ-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyRα3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR(1A)-GlyRα3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.

Molecular cloning and functional characterization of infectious PERV and development of diagnostic tests.

Pigs are the donor animals of choice for xenotransplantation (XTx) and xenogeneic cell therapy measurements. Most known porcine pathogens can be controlled by conventional means like vaccination, medication or specific pathogen-free breeding conditions. As pigs have co-evolved very closely with humans for a few millennia it is not very likely that even asymptomatic pathogens have escaped attention. Porcine endogenous retroviruses (PERV) are different from conventional pathogens as they are chromosomally fixed in every cell of the animal, hence PERV cannot be easily controlled. While PERV show no phenotype in the porcine host, recent data demonstrate that some polytropic proviruses can be activated by external stimuli and that those can productively infect human cells in vitro. In evaluation of the retrovirological safety of XTx, we determined the number of replication-competent PERV to be limited and to exhibit a heterogeneous distribution, therefore suggesting that they could be removed by conventional breeding. The transcriptional regulation of some PERV due to repetitive elements in their long terminal repeats enables their adaptation to new host cells. The diagnostic tools available, based on immunological and polymerase chain reaction techniques, were shown to be sensitive in both the animal and in vitro, but must still show their potential in human XTx recipients, where they are confronted with very low antigen expression and the phenomenon of microchimerism.