Endogenous benzodiazepine site peptide ligands operating bidirectionally in vivo in neurogenesis and thalamic oscillations.
By binding to the benzodiazepine site, diazepam binding inhibitor (DBI) is associated with negative allosteric modulation (NAM) of GABAA receptors (Costa and Guidotti in Life Sci 49:325-344, 1991). However, the demonstration of a true physiological role of DBI and its fragments has only recently been reported. Based on DBI gain- and loss-of-function experiments in vivo, DBI and its fragment ODN were found to promote neurogenesis in the subventricular zone in vivo. Acting as NAM on GABAA receptors of precursor cells, DBI counteracted the inhibitory effect of GABA and thereby enhanced the proliferation of these cells (Alfonso et al. in Cell Stem Cell 10:76-87, 2012). Conversely and most remarkably, in similar gain- and loss-of-function experiments in the thalamus, the DBI gene products acted as positive allosteric modulators (PAM) of GABAA receptors in prolonging the duration of IPSCs, an effect which was specific for GABA transmission within the reticular nucleus (nRT) (Christian et al. in Neuron 78:1063-1074, 2013). Since intra-nRT potentiation of GABA transmission by benzodiazepine drugs exerts powerful anti-oscillatory effects, DBI might be endogenously effective by modulating seizure susceptibility. It remains to be seen by which mechanism both NAM and PAM activity can arise from the Dbi gene. Nevertheless, the results open new perspectives on the regionally distinct endogenous modulation of GABA transmission via the benzodiazepine site.
Institute of Pharmacology and Neuroscience Center, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland, mohler@pharma.uzh.ch.
Hanns
H
Möhler
D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000378:metabolism*; D013788:Thalamus / Q000187:drug effects / Q000378:metabolism*
D026261:Diazepam Binding Inhibitor; D008024:Ligands; D010455:Peptides; D001569:Benzodiazepines