Rouwette T.,Max Planck Institute for Experimental Medicine |
Avenali L.,Max Planck Institute for Experimental Medicine |
Sondermann J.,Max Planck Institute for Experimental Medicine |
Narayanan P.,Max Planck Institute for Experimental Medicine |
And 4 more authors.
Channels | Year: 2015
In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles. © 2015 Taylor & Francis Group, LLC.
Tchumatchenko T.,Max Planck Institute for Dynamics and Self-Organization |
Tchumatchenko T.,Bernstein Center for Computational Neuroscience Goettingen |
Tchumatchenko T.,Collaborative Research Center 889 Cellular Mechanisms of Sensory Processing |
Wolf F.,Max Planck Institute for Dynamics and Self-Organization |
And 2 more authors.
PLoS Computational Biology | Year: 2011
Many sensory or cognitive events are associated with dynamic current modulations in cortical neurons. This raises an urgent demand for tractable model approaches addressing the merits and limits of potential encoding strategies. Yet, current theoretical approaches addressing the response to mean- and variance-encoded stimuli rarely provide complete response functions for both modes of encoding in the presence of correlated noise. Here, we investigate the neuronal population response to dynamical modifications of the mean or variance of the synaptic bombardment using an alternative threshold model framework. In the variance and mean channel, we provide explicit expressions for the linear and non-linear frequency response functions in the presence of correlated noise and use them to derive population rate response to step-like stimuli. For mean-encoded signals, we find that the complete response function depends only on the temporal width of the input correlation function, but not on other functional specifics. Furthermore, we show that both mean- and variance-encoded signals can relay high-frequency inputs, and in both schemes step-like changes can be detected instantaneously. Finally, we obtain the pairwise spike correlation function and the spike triggered average from the linear mean-evoked response function. These results provide a maximally tractable limiting case that complements and extends previous results obtained in the integrate and fire framework. © 2011 Tchumatchenko, Wolf.
Chapochnikov N.M.,University of Gottingen |
Chapochnikov N.M.,Max Planck Institute for Dynamics and Self-Organization |
Takago H.,University of Gottingen |
Huang C.-H.,University of Gottingen |
And 17 more authors.
Neuron | Year: 2014
The mechanisms underlying the large amplitudes and heterogeneity of excitatory postsynaptic currents (EPSCs) at inner hair cell (IHC) ribbon synapses are unknown. Based on electrophysiology, electron and superresolution light microscopy, and modeling, we propose that uniquantal exocytosis shaped by a dynamic fusion pore is a candidate neurotransmitter release mechanism in IHCs. Modeling indicated that the extended postsynaptic AMPA receptor clusters enable large uniquantal EPSCs. Recorded multiphasic EPSCs were triggered by similar glutamate amounts as monophasic ones and were consistent with progressive vesicle emptying during pore flickering. The fraction of multiphasic EPSCs decreased in absence of Ca2+ influx and upon application of the Ca2+ channel modulator BayK8644. Our experiments and modeling did not support the two most popular multiquantal release interpretations of EPSC heterogeneity: (1) Ca2+-synchronized exocytosis of multiple vesicles and (2) compound exocytosis fueled by vesicle-to-vesicle fusion. We propose that IHC synapses efficiently use uniquantal glutamate release for achieving high information transmission rates. © 2014 Elsevier Inc.