Nicotine-induced Ca2+-myristoyl Switch of Neuronal Ca2+ Sensor VILIP-1 in Hippocampal Neurons: A Possible Crosstalk Mechanism for Nicotinic Receptors
Signal Transduction Research Group, Neuroscience Research Center, Charité Universitaetsmedizin Berlin, Berlin, Germany. Cellular and Molecular Neurobiology
(Impact Factor: 2.51).
11/2008; 29(2):273-86. DOI: 10.1007/s10571-008-9320-z
Visinin-like protein (VILIP-1) belongs to the neuronal Ca2+ sensor family of EF-hand Ca2+-binding proteins that regulate a variety of Ca2+-dependent signal transduction processes in neurons. It is an interaction partner of alpha4beta2 nicotinic acetylcholine receptor (nAChR) and increases surface expression level and agonist sensitivity of the receptor in oocytes. Nicotine stimulation of nicotinic receptors has been reported to lead to an increase in intracellular Ca2+ concentration by Ca2+-permeable nAChRs, which in turn might lead to activation of VILIP-1, by a mechanism described as the Ca2+-myristoyl switch. It has been postulated that this will lead to co-localization of the proteins at cell membranes, where VILIP-1 can influence functional activity of alpha4-containing nAChRs. In order to test this hypothesis we have investigated whether a nicotine-induced and reversible Ca2+-myristoyl switch of VILIP-1 exists in primary hippocampal neurons and whether pharmacological agents, such as antagonist specific for distinct nAChRs, can interfere with the Ca2+-dependent membrane localization of VILIP-1. Here we report, that only alpha7- but not alpha4-containing nAChRs are able to elicit a Ca2+-dependent and reversible membrane-translocation of VILIP-1 in interneurons as revealed by employing the specific receptor antagonists dihydro-beta-erythroidine and methylallylaconitine. The nAChRs are associated with processes of synaptic plasticity in hippocampal neurons and they have been implicated in the pathology of CNS disorders, including Alzheimer's disease and schizophrenia. VILIP-1 might provide a novel functional crosstalk between alpha4- and alpha7-containing nAChRs.
Available from: Burt Sharp
- "Other genes in the Pink module are known to be involved in the neurobiological effects of nicotine. For example, the serotonin receptor 1 A (Htr1A) is modulated by chronic nicotine exposure , , and visinin-like 1, a neuronal calcium-sensing protein involved in nicotine-induced calcium signaling, induced the up-regulation of alpha4beta2 nicotinic acetylcholine receptors , . In summary, the Pink module, which is inversely correlated with nicotine intake in our study, contains 15 genes that are potentially associated with human smoking and the neuronal effects of nicotine. "
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ABSTRACT: Classical genetic studies show the heritability of cigarette smoking is 0.4-0.6, and that multiple genes confer susceptibility and resistance to smoking. Despite recent advances in identifying genes associated with smoking behaviors, the major source of this heritability and its impact on susceptibility and resistance are largely unknown. Operant self-administration (SA) of intravenous nicotine is an established model for smoking behavior. We recently confirmed that genetic factors exert strong control over nicotine intake in isogenic rat strains. Because the processing of afferent dopaminergic signals by nucleus accumbens shell (AcbS) is critical for acquisition and maintenance of motivated behaviors reinforced by nicotine, we hypothesized that differential basal gene expression in AcbS accounts for much of the strain-to-strain variation in nicotine SA. We therefore sequenced the transcriptome of AcbS samples obtained by laser capture microdissection from 10 isogenic adolescent rat strains and compared all RNA transcript levels with behavior. Weighted gene co-expression network analysis, a systems biology method, found 12 modules (i.e., unique sets of genes that covary across all samples) that correlated (p<0.05) with amount of self-administered nicotine; 9 of 12 correlated negatively, implying a protective role. PCR confirmed selected genes from these modules. Chilibot, a literature mining tool, identified 15 genes within 1 module that were nominally associated with cigarette smoking, thereby providing strong support for the analytical approach. This is the first report demonstrating that nicotine intake by adolescent rodents is associated with the expression of specific genes in AcbS of the mesolimbic system, which controls motivated behaviors. These findings provide new insights into genetic mechanisms that predispose or protect against tobacco addiction.
PLoS ONE 01/2014; 9(1):e86214. DOI:10.1371/journal.pone.0086214 · 3.23 Impact Factor
Available from: Burt Sharp
- "Vsnl1 interacts directly with the alpha4 subunit of the most abundant brain nicotinic cholinergic receptor (nAChR), alpha4beta2, increasing the surface expression of functional receptors, depending on Ca 2+ concentration (Zhao et al., 2009b). In contrast, alpha7- containing nAChRs elicit a calcium-dependent membrane localization of Vsnl1 (Zhao et al., 2009a). The inward Ca 2+ current induced by nicotinic stimulation of alpha7 nAChRs (Berg et al., 2006) may drive the activation and membrane localization of Vsnl1 that is associated with upregulation of alpha4beta2 nAChRs. "
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ABSTRACT: Inbred Lewis and Fisher 344 rat strains differ greatly in drug self-administration; Lewis rats operantly self-administer drugs of abuse including nicotine, whereas Fisher self-administer poorly. As shown herein, operant food self-administration is similar. On the basis of their pivotal role in drug reward, we hypothesized that differences in basal gene expression in GABAergic neurons projecting from nucleus accumbens (NAcc) to ventral pallidum (VP) play a role in vulnerability to drug-taking behavior. The transcriptomes of NAcc shell-VP GABAergic neurons from these two strains were analyzed in adolescents, using a multidisciplinary approach that combined stereotaxic ionotophoretic brain microinjections, laser-capture microdissection (LCM) and microarray measurement of transcripts. Laser-capture microdissection enriched the gene transcripts detected in gamma-aminobutyric acid (GABA) neurons compared to the residual NAcc tissue: a ratio of neuron/residual >1 and false discovery rate (FDR) <5% yielded 6623 transcripts, whereas a ratio of >3 yielded 3514. Strain-dependent differences in gene expression within GABA neurons were identified; 322 vs. 60 transcripts showed 1.5-fold vs. 2-fold differences in expression (FDR < 5%). Classification by gene ontology showed that these 322 transcripts were widely distributed, without categorical enrichment. This is most consistent with a global change in GABA neuron function. Literature mining by Chilibot found 38 genes related to synaptic plasticity, signaling and gene transcription, all of which determine drug abuse; 33 genes have no known association with addiction or nicotine. In Lewis rats, upregulation of Mint-1, Cask, CamkII , Ncam1, Vsnl1, Hpcal1 and Car8 indicates that these transcripts likely contribute to altered signaling and synaptic function in NAcc GABA projection neurons to VP.
Genes Brain and Behavior 07/2011; 10(7):778-88. DOI:10.1111/j.1601-183X.2011.00716.x · 3.66 Impact Factor
Available from: Michele H Jacob
- "We observed intense punctate labeling on both the soma and neurites of a subpopulation of neurons (Fig. 8a and b). Based on the labeling pattern found here and previous identification of hippocampal neuron subtypes that express functional α7 nAChRs (Buhler & Dunwiddie 2002, Szabo et al. 2008, Zhao et al. 2009), we predict that these cells are interneurons. Preincubating the cultured neurons with 10 μM α-BgTx reduced the intensity of the labeling to a level indistinguishable from background (Fig. 8c). "
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ABSTRACT: J. Neurochem. (2010) 114, 994–1006.
The α7* (*denotes the possible presence of additional subunits) nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the vertebrate nervous system and implicated in neuropsychiatric disorders that compromise thought and cognition. In this report, we demonstrate that the recently developed fluorescent ligand Cy3-ArIB[V11L;V16A] labels α7 nAChRs in cultured hippocampal neurons. However, photobleaching of this ligand during long image acquisition times prompted us to develop a new derivative. In photostability studies, this new ligand, Alexa Fluor 546-ArIB[V11L;V16A], was significantly more resistant to bleaching than the Cy3 derivative. The classic α7 ligand α-bungarotoxin binds to α1* and α9* nAChRs. In contrast, Alexa Fluor 546-ArIB[V11L;V16A] potently (IC50 1.8 nM) and selectively blocked α7 nAChRs but not α1* or α9* nAChRs expressed in Xenopus oocytes. Selectivity was further confirmed by competition binding studies of native nAChRs in rat brain membranes. The fluorescence properties of Alexa Fluor 546-ArIB[V11L;V16A] were assessed using human embryonic kidney-293 cells stably transfected with nAChRs; labeling was observed on cells expressing α7 but not cells expressing α3β2, α3β4, or α4β2 nAChRs. Further imaging studies demonstrate that Alexa Fluor 546-ArIB[V11L;V16A] labels hippocampal neurons from wild-type mice but not from nAChR α7 subunit-null mice. Thus, Alexa Fluor 546-ArIB[V11L;V16A] represents a potent and selective ligand for imaging α7 nAChRs.
Journal of Neurochemistry 08/2010; 114(4):994-1006. DOI:10.1111/j.1471-4159.2010.06819.x · 4.28 Impact Factor
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