1. Specific Effects of Phosphodiesterase Inhibitors in Striatum
Akinori Nishi, Mahomi Kuroiwa, Diane B. Miller, James P. O'Callaghan, Helen S. Bateup, Takahide Shuto, Naoki Sotogaku, Takaichi Fukuda, Nathaniel Heintz, Paul Greengard, and Gretchen L. Snyder
Signaling cascades involving cAMP mediate cellular responses to many extracellular signals in all cell types. To ensure specificity of action, the spatial and temporal extent of cAMP elevation must be tightly controlled. This is accomplished primarily by phosphodiesterases (PDEs), which degrade cAMP. PDEs comprise 11 families and >50 alternatively spliced variations whose intracellular expression is localized by sequestration and anchoring to scaffolding proteins. Thus, PDEs have targeted effects on specific signaling pathways, making them attractive drug targets. The striatum expresses an especially diverse group of PDEs, several of which have been proposed as targets for treating cognitive disorders. This week, Nishi et al. examine the differential localization and effects of two of these, PDE4 and PDE10A. PDE inhibitors affected dopamine- and adenosine-mediated signaling. PDE4 inhibitors altered signaling in presynaptic dopaminergic terminals, whereas PDE10A inhibitors acted only postsynaptically, where they enhanced signaling through dopamine D1 receptors and attenuated signaling through D2 receptors.
2. Regulation of Cav2.2 mRNA Stability by γ7 Protein
Laurent Ferron, Anthony Davies, Karen M. Page, David J. Cox, Jerôme Leroy, Dominic Waithe, Adrian J. Butcher, Priya Sellaturay, Steven Bolsover, Wendy S. Pratt, Fraser J. Moss, and Annette C. Dolphin
Transcriptional control of protein expression is widely studied, but an important determinant of the temporal extent of protein expression is mRNA turnover, the regulation of which is less well studied. Turnover is regulated in part by mRNA binding proteins, which can either enhance or inhibit degradation. These binding proteins can be regulated by extracellular signals, to prolong or terminate expression of specific proteins. Ferron et al. now report that two proteins, stargazin-like γ7 protein and heterogeneous ribonuclear protein A2 (hnRNP A2, previously implicated in stabilizing, trafficking, and enhancing translation of specific mRNAs), interact to control expression of the voltage-dependent calcium channel Cav2.2 by regulating its mRNA stability. hnRNP A2 binds to Cav2.2 mRNA, increasing mRNA stability and protein expression. γ7 binds to hnRNP A2, disrupting its interaction with Cav2.2 mRNA, which results in increased degradation of Cav2.2 mRNA (and other mRNAs to which hnRNP A2 binds) and decreased protein expression.
3. Reticulospinal Control of Escape
Tsunehiko Kohashi and Yoichi Oda
Sudden auditory or tactile stimuli create neuronal signals that are transmitted to the hindbrain reticular formation, which projects to spinal motor circuits and elicits protective behaviors. Such responses are readily elicited and are useful for studying the functional architecture of the reticulospinal pathway. For example, the relative simplicity of escape reflexes in fish—mediated by a pair of large, easily identifiable Mauthner neurons—has been particularly valuable in laying a foundation for studies of more complex motor control. Kohashi and Oda expand this foundation, using calcium imaging in intact larval zebrafish to measure the sensory responses of different types of reticulospinal neurons (RSNs). Auditory and tactile stimuli elicited similar tail-flip responses, but with different latencies. The stimuli activated different sets of RSNs: auditory stimuli activated Mauthner cells and produced short-latency escapes, whereas tactile stimuli activated homologous RSNs. These results show that related behavioral responses can be mediated by sensory inputs that segregate onto different sets of homologous RSNs.
4. VEGF-β-Mediated Attenuation of Motor Neuron Degeneration
Koen Poesen, Diether Lambrechts, Philip Van Damme, Joke Dhondt, Florian Bender, Nicolas Frank, Elke Bogaert, Bart Claes, Line Heylen, An Verheyen, Katrien Raes, Marc Tjwa, Ulf Eriksson, Masabumi Shibuya, Rony Nuydens, Ludo Van Den Bosch, Theo Meert, Rudi D'Hooge, Michael Sendtner, Wim Robberecht, and Peter Carmeliet
Several growth factors have shown promise for extending the life of motor neurons in amyotrophic lateral sclerosis (ALS), but the promise has faded because these factors fail to cross the blood–brain barrier or ventricle surface or because they have undesirable side effects. Poesen et al. suggest that vascular endothelial growth factor β (VEGF-β) may overcome these problems. VEGF-β enhanced survival in motor neuron cultures deprived of other growth factors similarly to brain-derived neurotrophic factor or ciliary neurotrophic factor. But unlike these other neuroprotective factors, VEGF-β and its homolog, VEGF, enter neural tissues from the CSF and can reach motor neurons in vivo. Intracerebroventricular delivery of VEGF or VEGF-β promoted motor neuron survival and increased longevity of SOD1-mutant rats, which have ALS-like degeneration. Unlike VEGF, however, VEGF-β did not promote angiogenesis and thus could potentially be used at a higher concentration to further increase survival.
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