1. Proton Inactivation of Choline Transporters
Choline transporters (CHTs) are concentrated at cholinergic nerve terminals at which these sodium-coupled transport molecules deliver the goods to the cytoplasm for subsequent acetylcholine (ACh) synthesis. Iwamoto et al. examined the biophysical properties of the human CHT expressed in Xenopus laevis oocytes. Several interesting properties emerged, including constitutive leakage current in the absence of substrate and variable stoichiometry of electrogenic transport. Their results may also solve a long-standing puzzle. Because CHTs can also transport ACh at high concentrations, and the transporters are highly expressed on presynaptic vesicles, transmitter could leak from ACh-containing synaptic vesicles. However, choline transport and current were inactivated at low pH. The authors hypothesize that the acidic pH in synaptic vesicles inactivates CHTs. However, once CHT-containing vesicles fuse with the plasma membrane, the neutral extracellular pH re-activates the transporter. It seems that CHTs come with a built-in ON–OFF switch.
2. MMP-2 and Wound Healing
Proteolysis is not always a bad thing, according to the results of Hsu et al. In the immediate aftermath of spinal cord injury, inhibition of metalloproteinases (MMPs) can improve recovery, but only if the treatment is limited to the first few days. This pattern suggests that some MMPs have a positive effect during the later stages of wound healing and repair. The authors put the hypothesis to the test, focusing on MMP-2. Mice subjected to moderate spinal cord contusion injury expressed MMP-2 during wound healing, primarily in reactive astrocytes. This expression appeared to be beneficial, because MMP-2 null mice were impaired in locomotor function. MMP-2 null mice also developed a more extensive astrocytic scar in the injured spinal cord. Because scar formation is thought to inhibit the regeneration of injured axons, MMP-2 may act to provide a cellular environment more conducive to wound healing.
3. Modulation of VPM Thalamic Units by the Locus Ceruleus
The noradrenergic neurons of the locus ceruleus (LC) influence sleep and wakefulness, as well as attention and feeding, through their diffuse projections. Devilbiss et al. sought to link the established cellular actions of norepinephrine to LC function. In a technical tour de force, the authors measured the effects of LC output on the sensory response properties of single neurons in the ventral posteriomedial (VPM) thalamus of awake, quietly resting rats. Microstimulation of the LC output enhanced norepinephrine influx in VPM and modulated the responses of individual units (neurons) to whiskerpad stimulation. Although units could show cell-specific behaviors, as a group, the responsiveness of VPM neurons was facilitated at low rates of LC stimulation but showed an inverted "U" response profile as LC stimulation increased. LC stimulation also altered correlated firing between groups of VPM neurons, effectively modulating their functional connectivity.
4. Cytosolic Dopamine and Synuclein Aggregation
This week, Mazzulli et al. explored the possible relationship between two events that can occur in Parkinson's disease (PD): a decline in cellular dopamine concentrations and an increase in aggregates containing á-synuclein. Mutations in the gene encoding á-synuclein are responsible for some cases of familial PD. A number of factors can affect the initiation of synuclein fibril formation. In cell-free systems, dopamine interacts with á-synuclein and inhibits fibril formation by stabilizing oligomeric á-synuclein intermediates. The authors developed a cellular model system to examine this interaction. They engineered neuroblastoma cells to express either wild-type or mutant á-synuclein and varying amounts of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. Retinoic acid-induced differentiation of cells expressing the A53T synuclein mutant increased synuclein aggregates. Increasing intracellular dopamine inhibited the transformation of mutant á-synuclein from soluble oligomers to Triton-insoluble aggregates.
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
Published on PsychCentral.com. All rights reserved.