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A glial variant of the vesicular monoamine transporter is required to store histamine in the Drosophila visual system.

Romero-Calderón R, Uhlenbrock G, Borycz J, Simon AF, Grygoruk A, Yee SK, Shyer A, Ackerson LC, Maidment NT, Meinertzhagen IA, Hovemann BT, Krantz DE - PLoS Genet. (2008)

Bottom Line: In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines.We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe.Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

View Article: PubMed Central - PubMed

Affiliation: Gonda Goldschmied Center for Neuroscience and Genetics Research, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

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dVMAT mutant heads store less histamine than controls.(A) Histamine content is decreased by 30% in the homozygous dVMATP1 allele (P/P) and 47% in homozygotes of the dVMATΔ14 allele (Δ14) compared with the control line w1118Cs10 (w; +/+). Additional controls include a precise excision of the P in dVMATP1 (p.e.) and dVMATP1 heterozygotes (P/+); one-way ANOVA p<0.0001, with Bonferroni post-hoc test used to compare all data. Differences in head histamine from w;+/+ are indicated as **, p<0.01 and ***, p<0.001. Bars show the mean±SEM of independent trials measuring 3–4 heads/trial of randomly mixed sexes, with the number of trials (n) indicated in the bars. (B) Genetic rescue of dVMAT-B. All lines are in a genetic background containing the transgene repo-Gal4/+, and the genotype of the line used as a baseline control is dVMATP1/+; repo-Gal4/+ (indicated as “Base. P/+; Repo/+”). In this background, histamine content is reduced 45% by rendering the dVMATP1 allele homozygous (dVMATP1/dVMATP1; repo-Gal4/+, indicated as “Mut. P/P; Repo/+”. Rescue was performed using repo-Gal4 with two separate UAS-dVMAT-B transgenes, UAS-dVMAT-B1 and -B2, indicated as “Res.1 P/P; Repo/B1” and “Res.2 P/P; Repo/B2”, respectively. Additional controls include dVMATP1 heterozygotes with repo-Gal4 and either UAS-dVMAT-B1 or -B2, (indicated as “Con.1 P/+; Repo/B1”, and “Con.2 P/+; Repo/B2”). One-way ANOVA (p<0.0006, with Dunnett's multiple comparison tests) shows that “Mut.” head histamine content differs from all other lines (p<0.05: *). Bars show mean±SEM of independent trials measuring 4 heads, of randomly mixed sexes, with the number of trials indicated in the bars.
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pgen-1000245-g008: dVMAT mutant heads store less histamine than controls.(A) Histamine content is decreased by 30% in the homozygous dVMATP1 allele (P/P) and 47% in homozygotes of the dVMATΔ14 allele (Δ14) compared with the control line w1118Cs10 (w; +/+). Additional controls include a precise excision of the P in dVMATP1 (p.e.) and dVMATP1 heterozygotes (P/+); one-way ANOVA p<0.0001, with Bonferroni post-hoc test used to compare all data. Differences in head histamine from w;+/+ are indicated as **, p<0.01 and ***, p<0.001. Bars show the mean±SEM of independent trials measuring 3–4 heads/trial of randomly mixed sexes, with the number of trials (n) indicated in the bars. (B) Genetic rescue of dVMAT-B. All lines are in a genetic background containing the transgene repo-Gal4/+, and the genotype of the line used as a baseline control is dVMATP1/+; repo-Gal4/+ (indicated as “Base. P/+; Repo/+”). In this background, histamine content is reduced 45% by rendering the dVMATP1 allele homozygous (dVMATP1/dVMATP1; repo-Gal4/+, indicated as “Mut. P/P; Repo/+”. Rescue was performed using repo-Gal4 with two separate UAS-dVMAT-B transgenes, UAS-dVMAT-B1 and -B2, indicated as “Res.1 P/P; Repo/B1” and “Res.2 P/P; Repo/B2”, respectively. Additional controls include dVMATP1 heterozygotes with repo-Gal4 and either UAS-dVMAT-B1 or -B2, (indicated as “Con.1 P/+; Repo/B1”, and “Con.2 P/+; Repo/B2”). One-way ANOVA (p<0.0006, with Dunnett's multiple comparison tests) shows that “Mut.” head histamine content differs from all other lines (p<0.05: *). Bars show mean±SEM of independent trials measuring 4 heads, of randomly mixed sexes, with the number of trials indicated in the bars.

Mentions: To quantify the contribution of DVMAT to histamine storage more accurately, we used high performance liquid chromatography (HPLC) to measure the total histamine content in dVMAT mutant heads (Figure 8A). As controls, we used: 1) w1118Cs10 (w; +/+), the genetic background into which dVMATP1 had been out-crossed; 2) a precise excision of the P element in l(2)SHO459 (p.e.); and 3) dVMATP1 heterozygotes (P/+). The histamine content in heads derived from the three control lines—w1118Cs10, p.e., and P/+—was 6±0.4, 5.9±0.4 and 6.1±0.3 and ng/head respectively. In contrast, the dVMATP1 (P/P) homozygotes contained 4.2±0.2 ng/head, a 30% reduction relative to the controls (Bonferroni post-test, p<0.01). The homozygous imprecise excision (dVMATΔ14, “Δ14” in Figure 8A), contained 3.2±0.5 ng/head, a 47% reduction relative to controls (Bonferroni post-test, p<0.001). These data indicate that dVMAT plays an unexpectedly important role in regulating the histamine content of the head, and together with the results from our histamine labelings they indicate that this role is exerted on the visual system by means of the fenestrated glia.


A glial variant of the vesicular monoamine transporter is required to store histamine in the Drosophila visual system.

Romero-Calderón R, Uhlenbrock G, Borycz J, Simon AF, Grygoruk A, Yee SK, Shyer A, Ackerson LC, Maidment NT, Meinertzhagen IA, Hovemann BT, Krantz DE - PLoS Genet. (2008)

dVMAT mutant heads store less histamine than controls.(A) Histamine content is decreased by 30% in the homozygous dVMATP1 allele (P/P) and 47% in homozygotes of the dVMATΔ14 allele (Δ14) compared with the control line w1118Cs10 (w; +/+). Additional controls include a precise excision of the P in dVMATP1 (p.e.) and dVMATP1 heterozygotes (P/+); one-way ANOVA p<0.0001, with Bonferroni post-hoc test used to compare all data. Differences in head histamine from w;+/+ are indicated as **, p<0.01 and ***, p<0.001. Bars show the mean±SEM of independent trials measuring 3–4 heads/trial of randomly mixed sexes, with the number of trials (n) indicated in the bars. (B) Genetic rescue of dVMAT-B. All lines are in a genetic background containing the transgene repo-Gal4/+, and the genotype of the line used as a baseline control is dVMATP1/+; repo-Gal4/+ (indicated as “Base. P/+; Repo/+”). In this background, histamine content is reduced 45% by rendering the dVMATP1 allele homozygous (dVMATP1/dVMATP1; repo-Gal4/+, indicated as “Mut. P/P; Repo/+”. Rescue was performed using repo-Gal4 with two separate UAS-dVMAT-B transgenes, UAS-dVMAT-B1 and -B2, indicated as “Res.1 P/P; Repo/B1” and “Res.2 P/P; Repo/B2”, respectively. Additional controls include dVMATP1 heterozygotes with repo-Gal4 and either UAS-dVMAT-B1 or -B2, (indicated as “Con.1 P/+; Repo/B1”, and “Con.2 P/+; Repo/B2”). One-way ANOVA (p<0.0006, with Dunnett's multiple comparison tests) shows that “Mut.” head histamine content differs from all other lines (p<0.05: *). Bars show mean±SEM of independent trials measuring 4 heads, of randomly mixed sexes, with the number of trials indicated in the bars.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2570955&req=5

pgen-1000245-g008: dVMAT mutant heads store less histamine than controls.(A) Histamine content is decreased by 30% in the homozygous dVMATP1 allele (P/P) and 47% in homozygotes of the dVMATΔ14 allele (Δ14) compared with the control line w1118Cs10 (w; +/+). Additional controls include a precise excision of the P in dVMATP1 (p.e.) and dVMATP1 heterozygotes (P/+); one-way ANOVA p<0.0001, with Bonferroni post-hoc test used to compare all data. Differences in head histamine from w;+/+ are indicated as **, p<0.01 and ***, p<0.001. Bars show the mean±SEM of independent trials measuring 3–4 heads/trial of randomly mixed sexes, with the number of trials (n) indicated in the bars. (B) Genetic rescue of dVMAT-B. All lines are in a genetic background containing the transgene repo-Gal4/+, and the genotype of the line used as a baseline control is dVMATP1/+; repo-Gal4/+ (indicated as “Base. P/+; Repo/+”). In this background, histamine content is reduced 45% by rendering the dVMATP1 allele homozygous (dVMATP1/dVMATP1; repo-Gal4/+, indicated as “Mut. P/P; Repo/+”. Rescue was performed using repo-Gal4 with two separate UAS-dVMAT-B transgenes, UAS-dVMAT-B1 and -B2, indicated as “Res.1 P/P; Repo/B1” and “Res.2 P/P; Repo/B2”, respectively. Additional controls include dVMATP1 heterozygotes with repo-Gal4 and either UAS-dVMAT-B1 or -B2, (indicated as “Con.1 P/+; Repo/B1”, and “Con.2 P/+; Repo/B2”). One-way ANOVA (p<0.0006, with Dunnett's multiple comparison tests) shows that “Mut.” head histamine content differs from all other lines (p<0.05: *). Bars show mean±SEM of independent trials measuring 4 heads, of randomly mixed sexes, with the number of trials indicated in the bars.
Mentions: To quantify the contribution of DVMAT to histamine storage more accurately, we used high performance liquid chromatography (HPLC) to measure the total histamine content in dVMAT mutant heads (Figure 8A). As controls, we used: 1) w1118Cs10 (w; +/+), the genetic background into which dVMATP1 had been out-crossed; 2) a precise excision of the P element in l(2)SHO459 (p.e.); and 3) dVMATP1 heterozygotes (P/+). The histamine content in heads derived from the three control lines—w1118Cs10, p.e., and P/+—was 6±0.4, 5.9±0.4 and 6.1±0.3 and ng/head respectively. In contrast, the dVMATP1 (P/P) homozygotes contained 4.2±0.2 ng/head, a 30% reduction relative to the controls (Bonferroni post-test, p<0.01). The homozygous imprecise excision (dVMATΔ14, “Δ14” in Figure 8A), contained 3.2±0.5 ng/head, a 47% reduction relative to controls (Bonferroni post-test, p<0.001). These data indicate that dVMAT plays an unexpectedly important role in regulating the histamine content of the head, and together with the results from our histamine labelings they indicate that this role is exerted on the visual system by means of the fenestrated glia.

Bottom Line: In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines.We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe.Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

View Article: PubMed Central - PubMed

Affiliation: Gonda Goldschmied Center for Neuroscience and Genetics Research, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

ABSTRACT
Unlike other monoamine neurotransmitters, the mechanism by which the brain's histamine content is regulated remains unclear. In mammals, vesicular monoamine transporters (VMATs) are expressed exclusively in neurons and mediate the storage of histamine and other monoamines. We have studied the visual system of Drosophila melanogaster in which histamine is the primary neurotransmitter released from photoreceptor cells. We report here that a novel mRNA splice variant of Drosophila VMAT (DVMAT-B) is expressed not in neurons but rather in a small subset of glia in the lamina of the fly's optic lobe. Histamine contents are reduced by mutation of dVMAT, but can be partially restored by specifically expressing DVMAT-B in glia. Our results suggest a novel role for a monoamine transporter in glia that may be relevant to histamine homeostasis in other systems.

Show MeSH