of the Max - MDC

Structure of the Group
Group Leader
Jr.-Prof. Dr. Jochen C. Meier*
Graduate Students
Sabrina Eichler*
Philipp Schäfermeier*
Technical Assistants
Carola Bernert*
Silke Otto*
* part of the period reported (from mid-2006 to present)
A
C
E
D
F
B
isolated mRNAs encoding gain-of-function glycine receptors
with substantially increased apparent affinities for glycine
(Figure 1A-C) and taurine, which renders them well suited
for translation of ambient hippocampal neurotransmitters
into tonic inhibition. We could establish that high affinity
glycine receptors arise from post-transcriptional C-to-U RNA
editing (Figure 1D), as demonstrated by the absence of
encoding genomic sequences (Figure 1E). Furthermore, the
C-to-U RNA editing inhibitor zebularine was found to be
effective on tonic glycinergic currents elicited in hippocampal
neurons (Figure 1F). Having these tools in hands, functional
analysis was performed at a cellular level, using high
affinity receptor expression in primary hippocampal neurons,
and at a systemic level, using high affinity receptor
screening of resected hippocampi from mesial temporal lobe
epilepsy (TLE) patients. In addition, potential effects of
high affinity glycine receptor activation on network oscillatory
activity were investigated in the kainate mouse model
of TLE. So far, our data all point to a compensatory and
homeostatic, but pathophysiological, role of high affinity
glycine receptor activation in the course of TLE. Therefore,
we are interested in developing this novel functional glycine
receptor property into novel pharmacological approaches to
the treatment of hyperexcitability disorders.
High affinity glycine receptors. (A, B) Dose response curves illustrating substantially
increased apparent affinities of RNA-edited glycine receptors (α2A 192L , α2B 192L , α3 185L )
for glycine. (C) Glycine receptor schematic delineating the glycine binding pocket.
The amino acid substitution P185L (α3) and P192L (α2) that is generated by RNA
editing is situated outside the glycine binding pocket, suggesting conformational
rearrangements. (D) C-to-U RNA editing is catalyzed by enzymes that convert cytidine
into uracil by deamination. Zebularine is an transition state inhibitor of cytidine deaminases.
(E) Genomic GLRA2 sequence around the RNA-edited position, obtained
from a male temporal lobe epilepsy patient with a severe course of disease. Note the
lack of leucine-encoding sequences. Instead, the CCC-triplet codes for proline at position
185 within the mature glycine receptor protein. (F) Inhibition of cytidine deaminases
in brain slices reveals the magnitude of tonic inhibition carried by high affinity
glycine receptors.
Selected Publications
Lardi-Studler, B, Smolinsky, B, Petitjean, CM, Koenig, F, Sidler,
C, Meier, JC, Fritschy, J-M, Schwarz, G. (2007). Vertebrate-specific
sequences in gephyrin E-domain regulate cytosolic
aggregation and postsynaptic clustering. J. Cell Sci. 120,1371-
1382.
Meier JC. (2006). Protein Kinases and synaptogenesis. In:
Molecular Mechanisms of synaptogenesis (Dityatev A, El-
Husseini A, eds), pp 311-332. Springer Press.
Singh, B, Henneberger, C, Betances, D, Arevalo, MA, Rodriguez-
Tebar, A, Meier, JC, Grantyn, R. (2006). Altered balance of glutamatergic/GABAergic
synaptic input and associated changes in
dendrite morphology after BDNF expression in BDNF-deficient
hippocampal neurons. J. Neurosci. 26,7189-7200.
Meier, JC, Henneberger, C, Melnick, I, Racca, C, Harvey, RJ,
Heinemann, U, Schmieden V, Grantyn, R. (2005). RNA editing
produces P185L amino acid substitution in glycine receptor a3
resulting in high agonist potency. Nature Neurosci. 8,736-744.
Jüttner, R, Moré, MI, Das, D, Babich, A, Meier, J, Henning, M,
Erdmann, B, Müller, E-C, Otto, A, Grantyn, R, Rathjen, FG.
(2005). Impaired synapse function during postnatal development
in the absence of CALEB, an EGF-like protein processed by
activity. Neuron 46,233-245.
182 Function and Dysfunction of the Nervous System