Research

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.

Model Systems for Membrane Signaling

Model of an AMPA receptor complex

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:

AMPAR-type glutamate receptors (AMPARs) and HCN channels

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.

GABA_B-type GPCRs and BK_Ca-Cav signaling supercomplexes

Molecular model of a BK-Cav channel complex

In the cellular context, the signal transduction of both GABA_B receptors and Ca²⁺-activated K⁺ channels of the BK_Ca-type occurs in association with partner proteins upon formation of signaling supercomplexes.

With GABA_B these supercomplexes consist of GABA_B1, GABA_B2, hetero­trimeric G-proteins and four members of the KCTD-family of proteins; these KCTD proteins that we recently identified as novel GABA_B receptor constituents determine the time course and speed of the receptor-mediated signalling [Schwenk et al., Nature, 2010].

BK_Ca 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 BK_Ca channel; together this supercomplex translates a local Ca²⁺ influx into a precisely timed hyperpolarization [Berkefeld et al., Science, 2006].

Cav2 voltage-gated Ca²⁺channels

Model of Cav2 channel networks in the pre-synapse

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].