PCP2 Shapes Light Response of ON Bipolar Cells
Ying Xu, Pyroja Sulaiman, Rod Feddersen, Jian Liu, Robert G. Smith, and Noga Vardi
(see pages 8873–8884)
Activation of G-protein-coupled receptors (e.g., metabotropic glutamate receptors in retinal ON bipolar cells) causes GTP to bind to the G-protein in place of GDP, resulting in dissociation and activation of Gα and Gβγ subunits and subsequent downstream effects (e.g., closing of cation channels). The speed and duration of subunit activation are regulated by proteins that facilitate or inhibit GTP–GDP exchange. One such protein is PCP2, found exclusively in ON bipolar cells and cerebellar Purkinje cells. Xu et al. report that a unique splice variant of PCP2 is expressed in all rod and some cone ON bipolar cells in mice. PCP2-null bipolar cells had a more depolarized resting potential and greater inward current when clamped at −60 mV than wild type, suggesting that PCP2 increases the fraction of closed cation channels in the dark. In response to light, null cells had a slower rise and longer decay, suggesting that PCP2 speeds the light response.
FGF2 Causes NCAM Palmitoylation
Evgeni Ponimaskin, Galina Dityateva, Mika O. Ruonala, Masaki Fukata, Yuko Fukata, Fritz Kobe, Fred S. Wouters, Markus Delling, David S. Bredt, Melitta Schachner, and Alexander Dityatev
(see pages 8897–8907)
Protein palmitoylation, in which a fatty acid is linked to a cysteine residue, regulates many proteins involved in neuronal development and synaptogenesis. This week, Ponimaskin et al. show that fibroblast growth factor 2 (FGF2) induces palmitoylation of two transmembrane isoforms of neural cell adhesion molecule (NCAM) in mouse hippocampal neurons. Palmitoylation increased the fraction of NCAM localized to cholesterol- and sphingolipid-rich membrane domains called lipid rafts, and palmitoylation of both NCAM140 and NCAM180 was required for stimulation of neurite outgrowth by FGF2. FGF2 stimulation of neurite growth also required fyn tyrosine kinase and protein kinase C, downstream effectors of NCAM signaling. The palmitoyl transferase DHHC-7 likely mediates FGF2-induced palmitoylation of NCAM, because DHHC-7 overexpression stimulated neurite growth and FGF2 occluded this effect. These results, along with previous studies, suggest that NCAM palmitoylation is a common means of linking long-range (growth factor) growth signals to local (adhesion molecule) signals.
Prenatal Stress Alters Future Brain Development
Bridget R. Mueller and Tracy L. Bale
(see pages 9055–9065)
Prenatal stress increases the risk of developing psychiatric disorders, including depression, autism, and schizophrenia. In this issue, Mueller and Bale show that male (but not female) mice subjected to stress early in gestation exhibited increased maladaptive coping responses in tail-suspension and forced-swim tests. Because gestational stress exerted its effects before the brain had formed, the authors examined changes in placental protein expression that might alter future development. Levels of several growth factors were elevated in males and reduced in females. Notably, a protein that helps maintain appropriate DNA methylation (and therefore proper transcriptional control) was significantly lower in control and stressed male placentas than in females. Thus, stress may impact transcriptional regulation more in males than in females. Indeed, stress decreased methylation of DNA encoding the stress-related protein corticotropin-releasing factor (CRF) in prenatally stressed males, and as adults, these mice had elevated CRF and larger increases in corticosterone following restraint stress.
Neurobiology of Disease
Intrabodies Reduce Mutant Huntingtin Levels
Amber L. Southwell, Ali Khoshnan, Denise Dunn, Charles W. Bugg, Donald C. Lo, and Paul H. Patterson
(see pages 9013–9020)
Many neurodegenerative diseases, including Huntington's disease (HD), are caused by the addition of polyglutamine repeats to a specific protein. In HD, polyglutamine expansion in huntingtin causes aggregation, sequestration of other proteins, and disruption of proteasome-mediated protein degradation. Although mutated huntingtin is expressed widely, only a subset of neurons degenerates, possibly because toxicity is modulated by protein domains surrounding the polyglutamine expansion. Targeting these domains with highly specific intracellular antibodies (intrabodies) might therefore be an effective treatment for HD. Southwell et al. have tested intrabodies targeting different regions of mutant huntingtin, and found that they differed both in their ability to decrease toxicity in cortico-striatal brain slices and in their apparent mechanism of action. Several intrabodies decreased levels and increased turnover of soluble mutant huntingtin, whereas another altered only subcellular distribution. Promisingly, huntingtin-clearing intrabodies did not significantly reduce levels of wild-type huntingtin, suggesting that they might eliminate mutant protein without disrupting normal cellular functions.