Our central goal is comprehensive understanding of organization and operation of rapid signal transduction and information processing at the plasma membrane of excitable cells under normal and pathophysiological conditions.
Perception and processing of biological information is mediated through rapid signal transduction processes at the plasma membrane of almost any type of cell – mostly through ion channels (controlled by transmembrane voltage and/or ligands) and G-protein coupled receptors (GPCRs). It has been a long-standing interest of this group to achieve profound insights into
- how these proteins work
- how they are organized at the plasma membrane
- how they realize the enormous specificity of their signaling in both time and space and
- how their signaling is endowed with activity-dependent "dynamics" required for adaptation and formation of memory.
As a fundamental step in pursuing these questions, latest molecular research using the approach of "functional proteomics" demonstrated that ion channels and GPCRs are not operating as stand-alone tools, rather their signaling results from multiple protein-protein interactions that occur in the "molecular environments" of channel and receptor proteins.
Conceptually, the arrangements of protein complexes, signaling super-complexes or protein networks represent the platforms for organization and operation of rapid signal transduction through channels and/or receptors: They modulate channel/receptor properties and processing, affect downstream pathways or shape spatio-temporal concentration gradients of ions and other diffusible messengers.
Although these insights have been promoted by analyses of quite a series of membrane proteins, we selected a few key players of neuronal signal transduction in synapses of CNS neurons as "model systems" for in-depth structural and functional investigations:
For both ion channels we have identified previously unknown auxiliary subunits, cornichon homologues for AMPARs [Schwenk et al., Science, 2009] and PEX5R/TRIP8b for HCNs [Zolles et al., Neuron, 2010]. These auxiliary subunits assemble with the pore-forming subunits into protein complexes and determine "gating" and "trafficking/processing" of the channels.
In the cellular context, the signal transduction of both GABAB receptors and Ca2+-activated K+ channels of the BKCa-type occurs in association with partner proteins upon formation of signaling supercomplexes.
With GABAB these supercomplexes consist of GABAB1, GABAB2, heterotrimeric G-proteins and four members of the KCTD-family of proteins; these KCTD proteins that we recently identified as novel GABAB receptor constituents determine the time course and speed of the receptor-mediated signalling [Schwenk et al., Nature, 2010].
BKCa channels, octamers of pore-forming and auxiliary subunits, co-assemble with up to four Cav channels that provide the Ca2+ required for reliable activation of the BKCa channel; together this supercomplex translates a local Ca2+ influx into a precisely timed hyperpolarization [Berkefeld et al., Science, 2006].
These channels, also known as P/Q-, N- and R-type channels, trigger quite a variety of cellular processes as a result of local Ca2+ influx. All of these functions, including vesicle release, control of excitation, gene expression and presynaptic plasticity, are mediated through extended protein networks
- that are assembled with and around the Cav
- that determine the cellular processes that can be initiated by Cav2 channel
activity and define the molecular framework for organization and operation of local Ca2+-signaling by Cav2 channels in the brain [Müller et al., PNAS, 2010].