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
Source: PubMed


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.

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    • "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 [78], [79], and visinin-like 1, a neuronal calcium-sensing protein involved in nicotine-induced calcium signaling, induced the up-regulation of alpha4beta2 nicotinic acetylcholine receptors [80], [81]. 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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    • "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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    • "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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