GABA(B) receptors are the G-protein-coupled receptors for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. They are expressed in almost all neurons of the brain, where they regulate synaptic transmission and signal propagation by controlling the activity of voltage-gated calcium (Ca(v)) and inward-rectifier potassium (K(ir)) channels. Molecular cloning revealed that functional GABA(B) receptors are formed by the heteromeric assembly of GABA(B1) with GABA(B2) subunits. However, cloned GABA(B(1,2)) receptors failed to reproduce the functional diversity observed with native GABA(B) receptors. Here we show by functional proteomics that GABA(B) receptors in the brain are high-molecular-mass complexes of GABA(B1), GABA(B2) and members of a subfamily of the KCTD (potassium channel tetramerization domain-containing) proteins. KCTD proteins 8, 12, 12b and 16 show distinct expression profiles in the brain and associate tightly with the carboxy terminus of GABA(B2) as tetramers. This co-assembly changes the properties of the GABA(B(1,2)) core receptor: the KCTD proteins increase agonist potency and markedly alter the G-protein signalling of the receptors by accelerating onset and promoting desensitization in a KCTD-subtype-specific manner. Taken together, our results establish the KCTD proteins as auxiliary subunits of GABA(B) receptors that determine the pharmacology and kinetics of the receptor response.

Large-conductance calcium- and voltage-activated potassium channels (BKCa) are dually activated by membrane depolarization and elevation of cytosolic calcium ions (Ca2+). Under normal cellular conditions, BKCa channel activation requires Ca2+ concentrations that typically occur in close proximity to Ca2+ sources. We show that BKCa channels affinity-purified from rat brain are assembled into macromolecular complexes with the voltage-gated calcium channels Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). Heterologously expressed BKCa-Cav complexes reconstitute a functional "Ca2+ nanodomain" where Ca2+ influx through the Cav channel activates BKCa in the physiological voltage range with submillisecond kinetics. Complex formation with distinct Cav channels enables BKCa-mediated membrane hyperpolarization that controls neuronal firing pattern and release of hormones and transmitters in the central nervous system.

The tungsten programme in ASDEX Upgrade is pursued towards a full high-Z device. The spectroscopic diagnostic and the cooling factor of W have been extended and refined. The W-coated surfaces represent now a fraction of 65 % (24.8 m 2). The only two major components which are not yet coated are the strikepoint region of the lower divertor as well as the limiters at the low field side. While extending the W surfaces, the W concentration and the discharge behaviour have changed gradually pointing to critical issues when operating with a W wall: anomalous transport in the plasma centre should not be too low, otherwise neoclassical accumulation can occur. A very successful remedy is the addition of central RF heating at the 20-30% level. Regimes with low ELM activity show increased impurity concentration over the whole plasma radius. These discharges can be cured by increasing the ELM frequency through pellet ELM pacemaking or by higher heating power. Moderate gas puffing also mitigates the impurity influx and penetration, however at the expense of lower confinement. The erosion yield at the low field side guard limiter can be as high as 10 3 and fast particle losses from NBI were identified to contribute a significant part to the W sputtering. Discharges run in the upper, W coated divertor do not show higher W concentrations than comparable discharges in the lower C-based divertor.