TY  - JOUR
A1  - Beck, Katherina
A1  - Ehmann, Nadine
A1  - Andlauer, Till F. M.
A1  - Ljaschenko, Dmitrij
A1  - Strecker, Katrin
A1  - Fischer, Matthias
A1  - Kittel, Robert J.
A1  - Raabe, Thomas
T1  - Loss of the Coffin-Lowry syndrome-associated gene RSK2 alters ERK activity, synaptic function and axonal transport in Drosophila motoneurons
JF  - Disease Models & Mechanisms
N2  - Plastic changes in synaptic properties are considered as fundamental for adaptive behaviors. Extracellular-signal-regulated kinase (ERK)-mediated signaling has been implicated in regulation of synaptic plasticity. Ribosomal S6 kinase 2 (RSK2) acts as a regulator and downstream effector of ERK. In the brain, RSK2 is predominantly expressed in regions required for learning and memory. Loss-of-function mutations in human RSK2 cause Coffin-Lowry syndrome, which is characterized by severe mental retardation and low IQ scores in affected males. Knockout of RSK2 in mice or the RSK ortholog in Drosophila results in a variety of learning and memory defects. However, overall brain structure in these animals is not affected, leaving open the question of the pathophysiological consequences. Using the fly neuromuscular system as a model for excitatory glutamatergic synapses, we show that removal of RSK function causes distinct defects in motoneurons and at the neuromuscular junction. Based on histochemical and electrophysiological analyses, we conclude that RSK is required for normal synaptic morphology and function. Furthermore, loss of RSK function interferes with ERK signaling at different levels. Elevated ERK activity was evident in the somata of motoneurons, whereas decreased ERK activity was observed in axons and the presynapse. In addition, we uncovered a novel function of RSK in anterograde axonal transport. Our results emphasize the importance of fine-tuning ERK activity in neuronal processes underlying higher brain functions. In this context, RSK acts as a modulator of ERK signaling.
KW  - mrsk2 KO mouse
KW  - S6KII RSK
KW  - transmission
KW  - neuromuscular junction
KW  - synapse
KW  - MAPK signaling
KW  - axonal transport
KW  - motoneuron
KW  - RSK
KW  - Drosophila
KW  - mechanisms
KW  - plasticity
KW  - protein kinase
KW  - signal transduction pathway
KW  - mitochondrial transport
KW  - glutamate receptor
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145185
VL  - 8
ER  - 
TY  - JOUR
A1  - Scholz, Nicole
A1  - Guan, Chonglin
A1  - Nieberler, Matthias
A1  - Grotmeyer, Alexander
A1  - Maiellaro, Isabella
A1  - Gao, Shiqiang
A1  - Beck, Sebastian
A1  - Pawlak, Matthias
A1  - Sauer, Markus
A1  - Asan, Esther
A1  - Rothemund, Sven
A1  - Winkler, Jana
A1  - Prömel, Simone
A1  - Nagel, Georg
A1  - Langenhan, Tobias
A1  - Kittel, Robert J
T1  - Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons
JF  - eLife
N2  - Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.
KW  - Latrophilin
KW  - adhesion GPCR
KW  - dCIRL
KW  - sensory physiology
KW  - metabotropic signalling
KW  - mechanotransduction
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170520
VL  - 6
IS  - e28360
ER  -