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102 records · Page 6Linked to original sources
PubMed2005

Alpha 2-adrenergic agonist enrichment of spinophilin at the cell surface involves beta gamma subunits of Gi proteins and is preferentially induced by the alpha 2A-subtype.

Agonist activation regulates reciprocal interactions of spinophilin and arrestin with the alpha2A- and alpha2B -adrenergic receptor (AR) subtypes via their 3i loop. Because arrestin association with G protein-coupled receptor is preceded by redistribution of arrestin to the cell surface, the present studies explored whether agonist activation of the alpha2A- and alpha2B -AR subtypes also led to spinophilin enrichment at the cell surface. Live cell imaging studies using a green fluorescent protein-tagged spinophilin examined spinophilin localization and its regulation by alpha2 -AR agonist. Agonist activation of alpha2A-AR preferentially, compared with the alpha2B-AR, led to spinophilin enrichment at the cell surface in human embryonic kidney 293 cells and in mouse embryo fibroblasts derived from spinophilin null mice. Activation of the delta LEESSSS alpha2A-AR, which has enriched association with spinophilin compared with the wild-type (WT) alpha2A-AR, does not show an enhanced redistribution of spinophilin to the surface compared with WT alpha2A-AR, demonstrating that the ability or affinity of the receptor in binding spinophilin may be independent of the ability of the receptor to effect spinophilin redistribution to the surface. Agonist-evoked enrichment of spinophilin at the cell surface seems to involve downstream signaling events, manifested both by the pertussis toxin sensitivity of the process and by the marked attenuation of spinophilin redistribution in cells expressing the beta-adrenergic receptor kinase-C tail, which sequesters beta gamma subunits of G proteins. Together, the data suggest that agonist-evoked spinophilin enrichment at the cell surface is caused by receptor-evoked signaling pathways and is independent of the affinity of the receptor for the spinophilin molecule.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2004

Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors.

Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with receptor-Gbetagamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of alpha2 adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.

Adenosine↗
PubMed2004

Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines.

OBJECTIVE: Aberrant synaptic connectivity may underlie the involvement of the hippocampus in schizophrenia. There is reasonable neuropathological evidence for a presynaptic pathology but few studies of the postsynaptic component. This study tested the hypothesis that hippocampal dendritic pathology is also present in schizophrenia. METHOD: Using in situ hybridization in sections of hippocampal formation from 10 patients with schizophrenia, 10 patients with mood disorders (three with bipolar disorder and seven with major depression), and 10 healthy comparison subjects, the authors examined the expression of two important dendritic genes: spinophilin, which serves as a marker of dendritic spines, and microtubule-associated protein 2 (MAP2), an overall dendritic marker. RESULTS: The patients with schizophrenia had lower levels of spinophilin mRNA in CA4 (hilus), CA3, the subiculum, and the entorhinal cortex than did the normal comparison subjects. The mood disorder group showed similar differences from the comparison group. MAP2 and cyclophilin mRNA did not differ between the groups in any subfield. CONCLUSIONS: Decreased spinophilin but unchanged MAP2 expression provides molecular evidence for a hippocampal dendritic pathology in schizophrenia that preferentially affects the spines. As spines are the target of most glutamatergic synapses, the data extend the evidence that excitatory synapses are particularly affected. Similar dendritic spine pathology may also occur in mood disorders.

Adult↗
PubMed2005

Dopaminergic abnormalities in select thalamic nuclei in schizophrenia: involvement of the intracellular signal integrating proteins calcyon and spinophilin.

OBJECTIVE: While both thalamic abnormalities and dopaminergic dysregulation have been separately implicated in the pathophysiology of schizophrenia, little is known about the possible dysfunction of molecules associated with dopaminergic neurotransmission in the thalamus in this illness. In this study, the authors studied this question by measuring in postmortem brain the expression of molecules associated with dopaminergic neurotransmission. METHOD: Using in situ hybridization and receptor autoradiography, the authors determined in schizophrenia and comparison subjects 1) thalamic expression of the transcripts encoding the five dopamine receptors; 2) binding to the dopamine D(1), D(2), and D(3) receptors; 3) monoaminergic innervation as assessed by binding to the vesicular monoamine transporter; and 4) transcripts encoding three dopamine receptor-associated intracellular proteins (calcyon, spinophilin, and DARPP-32) that mediate integration of dopaminergic signaling with other neurotransmitter systems. RESULTS: Both calcyon and spinophilin transcripts were significantly elevated in schizophrenia subjects. Monoaminergic innervation, as well as dopamine receptor transcripts and binding sites, were unaffected in this illness. CONCLUSIONS: These data indicate that there are dopaminergic abnormalities in the thalamus in schizophrenia but that they are at the level of intracellular integration of dopamine signaling with other neurotransmitter systems, likely including glutamate, in thalamic neurons.

Aged↗
PubMed2006

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice.

Stable tubule-only polypeptide (STOP) proteins are a family of microtubule associated proteins (MAPs) important in microtubule stabilization. Data indicating a role for microtubules in synaptic function has come from studies of the STOP null mouse, which exhibits synaptic deficits, in association with behavioural changes that are alleviated by antipsychotic treatment. These findings suggested that STOP mutant mice may be useful in studies of synaptic function, and could be especially relevant to schizophrenia, postulated to be a disorder of the synapse. Moreover, a genetic association between STOP and schizophrenia has been reported. This study aimed to further characterize synaptic alterations in STOP null and heterozygous mice. Using in situ hybridization histochemistry, the mRNA expression of three pre-synaptic (synaptophysin; growth associated protein-43 (GAP-43); vesicular glutamate transporter-1 (VGlut1)) and two post-synaptic (spinophilin; MAP2) proteins, was quantified in female STOP null (n = 7), heterozygous (n = 5) and wild type (n = 6) mice. For STOP null and heterozygous mice, synaptophysin, VGlut1, GAP-43 and spinophilin mRNAs were decreased in the hippocampus, whilst in addition in the null mice, synaptophysin, VGlut1 and spinophilin mRNAs were decreased in the cerebellum. Alterations in synaptic protein mRNA expression were also detected in the frontal and occipital cortex. MAP2 mRNA expression was unchanged in all brain regions. The profile of mRNA changes is broadly similar to that observed in schizophrenia. Together the data provide supporting evidence for a role for microtubules in synaptic function, and suggest that STOP, or other microtubule proteins, may contribute to the synaptic pathology of schizophrenia.

Animals↗
PubMed2003

Estradiol increases pre- and post-synaptic proteins in the CA1 region of the hippocampus in female rhesus macaques (Macaca mulatta).

The role of estrogen (E) in promoting learning and memory in females has been well studied in both rodent and primate models. In female rats, E increases dendritic spine number, synaptogenesis, and synaptic proteins in the CA1 region of the hippocampus, an area of the brain that mediates learning and memory. In the present study, we used radioimmunocytochemistry to examine whether E and progesterone were capable of modulating the levels of pre- and postsynaptic proteins in the CA1 region of the female nonhuman primate hippocampus. It was found that E increased syntaxin, synaptophysin (presynaptic), and spinophilin (postsynaptic) levels in the stratum oriens and radiatum of the CA1 region, whereas combined E and progesterone treatment decreased these synaptic proteins to the levels found in untreated, spayed controls. Furthermore, progesterone treatment alone significantly increased synaptophysin levels in the stratum oriens and radiatum of the CA1 region. The levels of these synaptic proteins were unaltered by hormone treatment in the dentate gyrus, suggesting that this steroid-induced plasticity is hippocampal region specific. As these synaptic proteins are important components of the synaptic apparatus and reliable markers of synaptogenesis, it appears that E-induced increases in cognitive function of higher order mammals may be mediated in part by the effect of E on hippocampal synaptogenesis and synaptic plasticity.

Animals↗
PubMed2001

Novel target sites for estrogen action in the dorsal hippocampus: an examination of synaptic proteins.

Structural studies have shown that estrogens increase dendritic spine number in the dorsal CA1 field of rat hippocampus using Golgi impregnation as well as the number of dorsal CA1 synapses visualized via electron microscopy. The present study was carried out to further these findings by examining changes in the levels of pre- and postsynaptic proteins using radioimmunocytochemistry (RICC). In this study, 2 days of estradiol-benzoate treatment produced significant and comparable increases in synaptophysin, syntaxin, and spinophilin immunoreactivity (IR) in the CA1 region of the dorsal hippocampus of ovariectomized female rats. For spinophilin, IR was also increased in the hilar region of the dentate gyrus as well as CA3. In all cases, the nonsteroidal estrogen antagonist CI628, which has been previously shown to block spine formation, inhibited the effects of estrogen. However, these protein differences were not detected in whole hippocampus using Western blots. These findings add to a growing body of evidence that estrogens increase synapses in the CA1 region of hippocampus along with changes in previously unidentified sites. These results also suggest that RICC is a rapid and sensitive method for examining molecular changes in synaptic profiles in anatomically distinct brain regions.

Animals↗
PubMed2002

The actin-binding domain of spinophilin is necessary and sufficient for targeting to dendritic spines.

Spinophilin is enriched in dendritic spines, small protrusions of the postsynaptic membrane along the length of the dendrite that contain the majority of excitatory synapses. Spinophilin binds to protein phosphatase 1 with high affinity and targets it to dendritic spines, therefore placing it in proximity to regulate glutamate receptor activity. Spinophilin also binds to and bundles f-actin, the main cytoskeletal constituent of dendritic spines, and may therefore serve to regulate the structure of the synapse. In this study, we sought to determine the structural basis for the targeting of spinophilin to dendritic spines. Our results show that the actin-binding domain of spinophilin is necessary and sufficient for targeting of spinophilin to dendrites and dendritic spines.

Actins↗
PubMed2004

Hippocampal synapses depend on hippocampal estrogen synthesis.

Estrogens have been described to induce synaptogenesis in principal neurons of the hippocampus and have been shown to be synthesized and released by exactly these neurons. Here, we have focused on the significance of local estrogen synthesis on spine synapse formation and the synthesis of synaptic proteins. To this end, we reduced hippocampal estrogen synthesis in vitro with letrozole, a reversible nonsteroidal aromatase inhibitor. In hippocampal slice cultures, letrozole treatment resulted in a dose-dependent decrease of 17beta-estradiol as quantified by RIA. This was accompanied by a significant decrease in the density of spine synapses and in the number of presynaptic boutons. Quantitative immunohistochemistry revealed a downregulation of spinophilin, a marker of dendritic spines, and synaptophysin, a protein of presynaptic vesicles, in response to letrozole. Surprisingly, no increase in the density of spines, boutons, and synapses and in spinophilin expression was seen after application of estradiol to the medium of cultures that had not been treated with letrozole. However, synaptophysin expression was upregulated under these conditions. Our results point to an essential role of endogenous hippocampal estrogen synthesis in the maintenance of hippocampal spine synapses.

Animals↗
PubMed2002

A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2.

The mechanisms establishing and maintaining dendritic spines in the mammalian CNS remain primarily unknown. We report a novel mechanism of neuronal spine plasticity in the developing preoptic area in which estradiol induces prostaglandin-E2 (PGE2) synthesis that in turn increases the density of spine-like processes. Estradiol requires PGE2 synthesis, in vivo and in vitro, and upregulates the dendritic spine protein spinophilin, an effect attenuated by antagonism of the AMPA-kainate receptor. This signaling pathway may involve cross talk between neighboring neurons and astrocytes and appears specific to the preoptic area in that hippocampal neurons responded with an increase in spinophilin to estradiol but not PGE2. Regionally specific mechanisms of estradiol-mediated synaptic plasticity allow for epigenetic control of complex sex-typic behaviors.

Animals↗