The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants

Zelano, Johan; Mikulovic, Sanja; Patra, Kalicharan; Kühnemund, Malte; Larhammar, Martin; Emilsson, Lina; Leão, Richardson N.; Kullander, Klas

doi:10.1016/j.expneurol.2012.09.006

Cited by 15 publications

(16 citation statements)

References 20 publications

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“…Slc10a4 Δ/Δ mice had significantly reduced ACh levels in the brainstem when compared with Slc10a4 +/+ mice (t-test, p < 0.01). Based on previous reports that SLC10A4 protein alters cholinergic function in the hippocampus (Zelano et al, 2013), we also measured acetylcholine levels in the hippocampus of Slc10a4 +/+ (n = 7) and Slc10a4 Δ/Δ (n = 10) mice (Fig. 5D).…”

Section: Resultsmentioning

confidence: 99%

“…The first evidence for a function of SLC10A4 in the brain was reported from the Kullander group (Zelano et al, 2013). They showed that mice lacking SLC10A4 had increased sensitivity to cholinergic stimulation resulting in decreased seizure threshold to cholinergic stimuli in hippocampal slices and increased sensitivity to the status epilepticus inducing cholinergic agent pilocarpine.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Melief

Gibbs

et al. 2016

Neuroscience

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An orphan member of the solute carrier family SLC10, SLC10A4 has been found to be enriched in midbrain and brainstem neurons and has been found to co-localize with and to affect dopamine homeostasis. We generated an SLC10A4 knockout mouse (Slc10a4Δ/Δ) using Cre targeted recombination, and characterized behavioral measures of motor and cognitive function as well as dopamine and acetylcholine levels in midbrain and brainstem. In agreement with previous studies, Slc10a4 mRNA was preferentially expressed in neurons in the brains of wild-type (Slc10a4+/+) mice and was enriched in dopaminergic and cholinergic regions. Slc10a4Δ/Δ mice had no impairment in motor function or novelty-induced exploratory behaviors but performed significantly worse in measures of spatial memory and cognitive flexibility. Slc10a4Δ/Δ mice also did not differ from Slc10a4+/+ in measures of anxiety. HPLC measures on tissue punches taken from the dorsal and ventral striatum reveal a decrease in dopamine content and a corresponding increase in the metabolite DOPAC, indicating an increase in dopamine turnover. Punches taken from the brainstem revealed a decrease in acetylcholine as compared with Slc10a4+/+ littermates. Together, these data indicate that loss of SLC10A4 protein results in neurotransmitter imbalance and cognitive impairment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Melief

Gibbs

et al. 2016

Neuroscience

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“…In the first study by Zelano et al [16], they analyzed whether the absence of SLC10A4 may have an impact on the function of the central cholinergic system. Injection of the cholinergic agonist pilocarpin induced status epilepticus earlier and more often in the Slc10a4 knockout mice compared with the wild type mice, suggesting that SLC10A4 may suppress epileptiform activity.…”

Section: Discussionmentioning

confidence: 99%

“…Injection of the cholinergic agonist pilocarpin induced status epilepticus earlier and more often in the Slc10a4 knockout mice compared with the wild type mice, suggesting that SLC10A4 may suppress epileptiform activity. They concluded that absence of the SLC10A4 protein results in cholinergic hypersensitivity of the knockout mice [16]. In a second study by Patra et al [17], the role of SLC10A4 on the structure and function of the neuromuscular junction was analyzed.…”

Section: Discussionmentioning

confidence: 99%

Expression, sorting and transport studies for the orphan carrier SLC10A4 in neuronal and non-neuronal cell lines and in Xenopus laevis oocytes

et al. 2015

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BackgroundSLC10A4 belongs to the solute carrier family SLC10 whose founding members are the Na+/taurocholate co-transporting polypeptide (NTCP, SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT, SLC10A2). These carriers maintain the enterohepatic circulation of bile acids between the liver and the gut. SLC10A4 was identified as a novel member of the SLC10 carrier family with the highest phylogenetic relationship to NTCP. The SLC10A4 protein was detected in synaptic vesicles of cholinergic and monoaminergic neurons of the peripheral and central nervous system, suggesting a transport function for any kind of neurotransmitter. Therefore, in the present study, we performed systematic transport screenings for SLC10A4 and also aimed to identify the vesicular sorting domain of the SLC10A4 protein.ResultsWe detected a vesicle-like expression pattern of the SLC10A4 protein in the neuronal cell lines SH-SY5Y and CAD. Differentiation of these cells to the neuronal phenotype altered neither SLC10A4 gene expression nor its vesicular expression pattern. Functional transport studies with different neurotransmitters, bile acids and steroid sulfates were performed in SLC10A4-transfected HEK293 cells, SLC10A4-transfected CAD cells and in Xenopus laevis oocytes. For these studies, transport by the dopamine transporter DAT, the serotonin transporter SERT, the choline transporter CHT1, the vesicular monoamine transporter VMAT2, the organic cation transporter Oct1, and NTCP were used as positive control. SLC10A4 failed to show transport activity for dopamine, serotonin, norepinephrine, histamine, acetylcholine, choline, acetate, aspartate, glutamate, gamma-aminobutyric acid, pregnenolone sulfate, dehydroepiandrosterone sulfate, estrone-3-sulfate, and adenosine triphosphate, at least in the transport assays used. When the C-terminus of SLC10A4 was replaced by the homologous sequence of NTCP, the SLC10A4-NTCP chimeric protein revealed clear plasma membrane expression in CAD and HEK293 cells. But this chimera also did not show any transport activity, even when the N-terminal domain of SLC10A4 was deleted by mutagenesis.ConclusionsAlthough different kinds of assays were used to screen for transport function, SLC10A4 failed to show transport activity for a series of neurotransmitters and neuromodulators, indicating that SLC10A4 does not seem to represent a typical neurotransmitter transporter such as DAT, SERT, CHT1 or VMAT2.

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“…The solute carrier family 10 member 4 (SLC10A4) is a synaptic vesicular protein that is co-expressed at high levels with markers of cholinergic and monoaminergic vesicles (Geyer et al, 2008;Burger et al, 2011;Larhammar et al, 2014) and was recently designated as vesicular aminergic-associated transporter (VAAT) because of its location in presynaptic vesicles of aminergic neurons and its modulation of amine neurotransmission (Larhammar et al, 2014). We recently used an Slc10a4 knockout mouse (herein referred to as Vaat KO) to study the functional and biological significance of this protein in central cholinergic neurotransmission (Zelano et al, 2013). These findings suggested a protective modulatory role for VAAT against susceptibility to cholinomimetic drugs in an induced epilepsy model.…”

Section: Introductionmentioning

confidence: 99%

A role for solute carrier family 10 member 4, or vesicular aminergic‐associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction

Patra

Lyons

Bauer

et al. 2014

Eur J of Neuroscience

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The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.

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The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants

Cited by 15 publications

References 20 publications

Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4

Expression, sorting and transport studies for the orphan carrier SLC10A4 in neuronal and non-neuronal cell lines and in Xenopus laevis oocytes

A role for solute carrier family 10 member 4, or vesicular aminergic‐associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction

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