1. Cav Shapes BKCa Kinetics
Henrike Berkefeld and Bernd Fakler
Large-conductance Ca2+- and voltage-activated potassium (BKCa) channels contribute to membrane repolarization after action potentials, shape dendritic spikes, and influence neurotransmitter release. Increasing intracellular calcium concentration shifts the activation potential of BKCa—which is essential for the channels to be activated at physiological voltages. A sufficient shift in activation potential occurs only when BKCa channels form complexes with voltage-activated calcium (Cav) channels. Now, Berkefeld and Fakler report that the onset and upward slope of BKCa activation—which varies widely across cell types—may largely be determined by which Cav channels the BKCa channels cluster with. When clustered with P/Q-type calcium channels(Cav2.1), BKCa activated at more hyperpolarized potentials and had a faster rise time than when clustered with L-type calcium channels (Cav1.2). The complexes also responded differently to simulated action potentials: action potentials with short duration reliably activated BKCa in BKCa–Cav2.1 complexes, whereas they often failed to activate BKCa in BKCa–Cav1.2 complexes.
2. NF-κB Phosphorylation State Determines Effect on Growth
Humberto Gutierrez, Gerard W. O'Keeffe, Núria Gavaldà, Denis Gallagher, and Alun M. Davies
The transcription factor nuclear factor κB (NF-κB) regulates many cellular functions, including neurite outgrowth from nodose ganglion neurons. Gutierrez et al. now report that NF-κB stimulates or inhibits neurite growth depending on the phosphorylation state of one amino acid. Superior cervical ganglion sympathetic neurons and nodose sensory neurons were cultured from neonatal mice and then transfected with proteins that either increased or decreased NF-κB-mediated transcription. In sympathetic neurons, NF-κB signaling was unnecessary for neurite growth, but enhancing NF-κB transcriptional activity inhibited neurite outgrowth. In sensory neurons, surprisingly, some treatments that enhanced NF-κB function increased neurite outgrowth, and others decreased outgrowth. These effects were traced to the activity of a kinase that phosphorylates NF-κB, which was constitutively active in sympathetic neurons. Eliminating the phosphorylation site on NF-κB prevented inhibition of neurite growth, whereas mutating it to mimic constitutive phosphorylation inhibited neurite growth in both sensory and sympathetic neurons.
3. Reward Activates Primary Somatosensory Cortex
Burkhard Pleger, Felix Blankenburg, Christian C. Ruff, Jon Driver, and Raymond J. Dolan
Receiving a reward activates sensory cortex, which might improve future performance, according to Pleger et al. Human subjects discriminated the frequency of two electrical stimuli applied to a finger. Before stimulation, a visual cue indicated the amount of reward given for a correct discrimination. After the subjects' response, a visual signal indicated whether they received the anticipated reward (for correct discrimination) or no reward (for incorrect answers). Functional magnetic resonance imaging revealed that finger stimulation activated primary somatosensory cortex (SI) similar amounts regardless of the size of the anticipated reward. Remarkably, however, SI was activated again by receipt of the reward, in proportion to the size of the reward. Moreover, after a reward was received, SI was more activated by stimulation on the next trial, and this effect was also larger for larger rewards. This reward-related activation, which was distinguishable from attention-related activation, was correlated with improved discrimination performance.
4. Proteasome Dysfunction Causes Neurodegeneration
Lynn Bedford, David Hay, Anny Devoy, Simon Paine, Des G. Powe, Rashmi Seth, Trevor Gray, Ian Topham, Kevin Fone, Nooshin Rezvani, Maureen Mee, Tim Soane, Robert Layfield, Paul W. Sheppard, Ted Ebendal, Dmitry Usoskin, James Lowe, and R. John Mayer
The ubiquitin proteasome system helps maintain cellular function by limiting the lifespan of regulatory proteins and degrading defective proteins. The addition of polyubiquitin chains to such proteins targets them for degradation by the 26S proteasome complex. Accumulation of ubiquitinated proteins characterizes many neurodegenerative diseases, including Parkinson's disease, suggesting that dysfunction of the proteasome system is involved in these diseases. But direct tests of this hypothesis have produced controversial results. This week, Bedford et al. provide definitive evidence that loss of proteasome function causes neurodegeneration. They produced mice in which an essential component of the 26S proteasome complex was conditionally knocked out in forebrain or substantia nigra neurons. This greatly reduced the number of 26S proteasome complexes in the affected neurons without affecting ubiquitin-independent degradation. Ubiquitinated proteins accumulated in the neurons, forming inclusions like those seen in neurodegenerative diseases, and this ultimately led to neurodegeneration and apoptosis.
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