Zhang V , Kucharski R , Landers C , Richards SN , Bröer S , Martin RE , Maleszka R .

	Figure 1. The honey bee dopamine transporter (AmDAT). (A) amdat gene model showing the exon and intron junctions of the full-length transcript and its spliced variant, the positions of methylated CpGs (black lollipops), and the regions of four amplicons (top) used for methylation analysis (see the main text and Supplementary Material for more details). The only methylated CpG uncovered by whole-genome methylomics is in exon 11. Protein coding exons are shown in green. (B) The predicted topologies of AmDAT (643 residues; shown in blue) and its splice variant AmDATΔex3 (598 residues; shown in orange). AmDATΔex3 lacks transmembrane domain 2 (TMD2) as well as the following cytosolic loop, resulting in an elongated TMD3. The affected region is shaded dark orange. The orientation of the N-terminus and TMD1 are predicted by TMpred and SPOCTOPUS to be inverted relative to the full-length protein.
	Figure 2. Heterologous expression of AmDAT and AmDATΔex3 in Xenopus oocytes. (A) Detection of HAEL2-AmDAT (∼55 kDa band indicated by black arrow) and HAEL2-AmDATΔex3 (∼50 kDa band indicated by black arrow) in oocyte membrane preparations. The samples were prepared on day 3 post-cRNA-injection, separated on a SDS-polyacrylamide gel, and probed with a mouse anti-HA antibody. A preparation of membrane protein from non-injected oocytes (ni) probed with the anti-HA antibody did not produce a band within this region. The image is representative of >3 independent experiments (performed using oocytes from different frogs). (B) Semi-quantification of the HAEL2-AmDAT and HAEL2-AmDATΔex3 proteins in the oocyte membrane. The intensity of the HAEL2-AmDATΔex3 band was expressed as a percentage of the band measured for HAEL2-AmDAT. The data are shown as the mean + SEM from six independent experiments (performed using oocytes from different frogs), within which measurements were averaged from two replicates. (C) Immunofluorescence microscopy of Xenopus oocytes expressing HAEL2-AmDAT or HAEL2-AmDATΔex3. The oocyte plasma membrane lies over a band of granules known as the “pigment layer”. This layer in turn surrounds a cytoplasm packed with yolk sacs and small endosomal- and lysosomal-type organelles. The expression of HAEL2-AmDAT resulted in a fluorescent band external to the pigment layer, consistent with this protein being present in the oocyte plasma membrane. A fluorescent band was not detected in non-injected oocytes or in oocytes expressing HAEL2-AmDATΔex3, suggesting that the splice variant is retained at an intracellular membrane. The images are representative of at least two independent experiments (performed using oocytes from different frogs), within which images were obtained from a minimum of 3 oocytes per oocyte type. (D) Transport of dopamine via AmDAT and HAEL2-AmDAT. Measurements of [3H]dopamine uptake by oocytes expressing the non-tagged or HA-tagged forms of AmDAT or AmDATΔex3 were performed on day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as the negative control. Dopamine uptake was expressed as a percentage of that measured in oocytes expressing AmDAT. The data are the mean + SEM of 3–4 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. The capacities of HAEL2-AmDAT and HAEL2-AmDATΔex3 for dopamine transport did not differ significantly from those of their non-tagged counterparts (p > 0.05), consistent with the HA-tag exerting little or no effect upon the functions of these proteins. ∗∗∗denotes a significant difference (p < 0.001) between the indicated treatments (one-way ANOVA).
	Figure 3. Transport properties of AmDAT in Xenopus oocytes. Measurements were conducted with oocytes expressing AmDAT on day 3 post-cRNA-injection. The oocytes were held at a membrane potential of –50 mV and superfused with ND96 (pH 7.4) or ND96 (pH 7.4) containing different monoamines at a final concentration of 100 μM. Each bar represents the mean and SEM of n = 11 oocytes (using oocytes from at least two different frogs). The data were normalised to the current induced by 100 μM dopamine. ∗∗∗denotes a significant difference (p < 0.001) from the dopamine current at 100 μM (one-way ANOVA). (A) Substrate specificity of AmDAT. (B) Inhibition of AmDAT by cocaine.
	Figure 4. AmDATΔex3 downregulates the AmDAT-mediated uptake of dopamine in Xenopus oocytes. Measurements of [3H]dopamine transport were performed on (A) day 1, (B) day 2, and (C) day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as a negative control, EmGFP and PfNT1 were included as co-injection controls, and oocytes expressing AmDAT served as the positive control. Dopamine uptake was expressed as a percentage of that measured in the AmDAT-expressing oocytes. The component of [3H]dopamine transport attributable to AmDAT was calculated by subtracting the background level of accumulation (i.e., dopamine uptake in non-injected oocytes) from that measured for each of the other oocyte types (the total levels of [3H]dopamine uptake are presented in Supplementary Figure S4). In all panels, the data are the mean + SEM of 3–10 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. ∗∗∗ denotes a significant difference (p < 0.001) from the positive control (one-way ANOVA).
	Figure 5. AmDATΔex3 downregulates AmDAT protein levels in Xenopus oocytes. The AmDAT-mediated transport of [3H]dopamine in oocytes expressing the HA-tagged forms of AmDAT or AmDATΔex3 was measured on (A) day 1 and (B) day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as a negative control, EmGFP and PfNT1 were included as co-injection controls, and oocytes expressing AmDAT served as the positive control. Dopamine uptake was expressed as a percentage of that measured in the AmDAT-expressing oocytes. In both panels, the data are the mean + SEM of 3–6 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. The capacity of HAEL2-AmDAT for dopamine transport, and the ability of HAEL2-AmDATΔex3 to downregulate AmDAT, did not differ significantly from that of its non-tagged counterpart (p > 0.05), consistent with the HA-tag exerting little or no effect upon the functions of these proteins. (C) Detection of the HAEL2-AmDAT (∼55 kDa band indicated by black arrow) and HAEL2-AmDATΔex3 (∼50 kDa band indicated by black arrow) proteins in oocyte membrane preparations. These western blot analyses were performed pairwise with the transport assays presented in panel (A). The samples were separated on a SDS-polyacrylamide gel and probed with a mouse anti-HA antibody. The image is representative of >3 independent experiments (performed using oocytes from different frogs) and is shown in full in Supplementary Figure S8. Semi-quantification of the (D,E) HAEL2-AmDAT and (F,G) HAEL2-AmDATΔex3 proteins in the oocyte membrane preparations was performed on day 1 panels (D,F) and day 3 panels (E,G) post-cRNA-injection. Protein band intensities were expressed as a percentage of that measured for the relevant positive control (i.e., oocytes expressing either HAEL2-AmDAT or HAEL2-AmDATΔex3). The data in panels (D–G) are shown as the mean + SEM from 3–8 independent experiments. ∗∗∗ denotes a significant difference (p < 0.001) from the relevant positive control (one-way ANOVAs).
	Figure 6. Interindividual variability in the expression of the amdat and amdatΔex3 transcripts. RNAs extracted from single brains were used for qPCR evaluation. Ten individuals were analyzed in each experiment. Refer to the Supplementary Material for further details.
	Figure S1. Cloning strategy of amdat and amdat∆ex3in. See a detailed description in Supplementary Data and Methods (page 3)
	Supplementary Figure 2. Total protein levels in the western blot analyses of oocytes expressing HAEL2-AmDAT or HAEL2-AmDATΔex3. (A) A representative image depicting the total protein present in samples prepared from oocytes expressing HAEL2-AmDAT or HAEL2-AmDATΔex3. Non-injected oocytes (ni) were included as a negative control. Preparations of oocyte membrane proteins were separated on a SDS-polyacrylamide gel and transferred to a nitrocellulose membrane. The proteins were visualised with the MemCodeTM reversible protein stain kit and the image is representative of n = 6. (B) The amount of protein present in each lane was semi-quantified using Image Studio Lite and the resulting values were expressed as a percentage of that measured for the HAEL2-AmDAT lane. Total protein levels are shown as the mean + SEM from 6 independent experiments performed on day 3 post-cRNA-injection. ns, no significant difference (p > 0.05) from the HAEL2-AmDAT lane (one-way ANOVAs).
	Figure S3A. Response of AmDAT to different concentrations of dopamine Oocytes were injected with AmDAT cRNA and incubated for 3 days. Subsequently, oocytes were held at a membrane potential of -50mV and superfused with ND96 (pH 7.4) alone or ND96 (pH 7.4) containing dopamine at final concentrations indicated above each peak in µM. Plot represents the responses of a single oocyte. Dop: dopamine
	Figure S3B. Inhibition of dopamine transport by AmDAT by the presence of cocaine. The figure presents an example of the inability of cocaine to produce a current in AmDAT expressing oocytes, supported by a significantly smaller normalised current (Mean 3.4 S.E.M. 1.7 p<0.001). Currents induced with a dopamine/cocaine mix were significantly smaller than currents induced by dopamine alone (Mean 61.6 S.E.M. 4.9 p < 0.001) (Figure 3), indicating the inhibition of AmDAT-mediated dopamine transport by cocaine. Currents could still be induced with dopamine after superfusion with cocaine or a dopamine/cocaine mix, showing that cocaine binds to AmDAT in a reversible manner.
	Supplementary Figure 4. The uptake of dopamine into oocytes co-expressing AmDAT and AmDATΔex3. Measurements of [3H]dopamine transport were performed on (A) day 1, (B) day 2, and (C) day 3 post-cRNA injection. Non-injected oocytes (ni) were included as a negative control, EmGFP and PfNT1 were included as co-injection controls, and oocytes expressing AmDAT served as the positive control. Dopamine uptake was expressed as a percentage of that measured in AmDAT-expressing oocytes. The rates of dopamine uptake (pmol per oocyte/h) in non-injected oocytes and oocytes expressing AmDAT were 0.33 ± 0.07 and 4.92 ± 1.11 (day 1), 0.34 ± 0.02 and 3.86 ± 1.63 (day 2), and 0.65 ± 0.09 and 7.07 ± 1.37 (day 3), respectively. The data are the mean + SEM of 3–10 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. *** denotes a significant difference (p < 0.001) from the positive control (one-way ANOVAs).
	Supplementary Figure 5. The uptake of hypoxanthine into Xenopus oocytes co-expressing PfNT1 with AmDAT or HAEL2-AmDAT. (A,B) Measurements of [3H]hypoxanthine transport were performed on days 1 and 3 post-cRNA-injection. Non-injected oocytes (ni) were included as a negative control, and oocytes expressing PfNT1 served as the positive control. Hypoxanthine uptake was expressed as a percentage of that measured in PfNT1-expressing oocytes. The rates of hypoxanthine uptake (pmol per oocyte/h) in non-injected oocytes and oocytes expressing PfNT1 were 1.01 ± 0.17 and 2.45 ± 0.34 (day 1), and 1.43 ± 0.40 and 4.30 ± 0.60 (day 3), respectively. (C,D) Using the data shown in panels (A,B), the component of [3H]hypoxanthine transport attributable to PfNT1 was calculated by subtracting the background level of accumulation (i.e. the uptake measured in non-injected oocytes) from that measured for each of the oocyte types. In both panels, the data are the mean + SEM of 3–4 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. ns, no significant difference (p > 0.05) in hypoxanthine accumulation relative to the PfNT1-expressing oocytes (one-way ANOVAs).
	Supplementary Figure 6. Semi-quantification of EmGFP expression in Xenopus oocytes. (A) Oocytes injected with 0–20 ng of EmGFP cRNA were lysed and the total fluorescence intensity (inset plot) measured using excitation and emission wavelengths of 487 nm and 509 nm, respectively. The component of fluorescence attributable to EmGFP (main plot) was calculated by subtracting the background level of fluorescence (i.e. the autofluorescence detected in lysates of non-injected oocytes) from that measured in lysates of oocytes expressing EmGFP. In both plots of (A), fluorescence was expressed as a percentage of that measured for the 10 ng treatment. The resulting plots revealed a sigmoidal relationship between the amount of EmGFP cRNA injected and the fluorescence intensity measured in the oocyte lysates (fourparameter logistic equation; R2 = 0.992). (B) In experiments performed pairwise with those presented in panel (A), the correlation between the amount of EmGFP cRNA injected and the resulting level of EmGFP expression was examined with a western blot protocol (Marchetti et al., 2015). Oocytes were injected with 0–20 ng of cRNA encoding EmGFP and whole oocyte extracts were prepared on day 3 post-cRNAinjection for analysis by western blot (using an anti-GFP antibody). The intensities of the resulting EmGFP bands were expressed as a percentage of that measured for the 10 ng treatment. Plotting these values against the amount of EmGFP cRNA injected revealed a sigmoidal relationship between the amount of EmGFP cRNA injected and the intensity of the EmGFP band (four-parameter logistic equation; R2 = 0.992). The relationship remained approximately linear when ≤ 10 ng of EmGFP cRNA was injected into the oocytes. The relationship remained approximately linear when ≤ 10 ng of EmGFP cRNA was injected into the oocytes. (C) Combining plots (A,B) over the 0–10 ng treatments confirmed a positive correlation (R2 = 0.989) between EmGFP band intensity and EmGFP fluorescence intensity. Taken together, these datasets indicated that measurements of EmGFP fluorescence intensity can be used to quantify EmGFP protein expression in the lysates of oocytes injected with ≤ 10 ng of EmGFP cRNA. In all panels, the data are the mean ± SEM of 3–5 independent experiments (performed using oocytes from different frogs) and were undertaken on day 3 post-cRNA-injection.
	Supplementary Figure 7. Co-expression of EmGFP with AmDAT or AmDATΔex3 in Xenopus oocytes. Lysates of oocytes co-expressing EmGFP with AmDAT, HAEL2-AmDAT, or AmDATΔex3 were prepared on days 1–3 post-cRNA-injection. The negative controls included non-injected oocytes as well as oocytes expressing AmDAT or AmDATΔex3, and oocytes expressing EmGFP served as the positive control. (A–C) Fluorescence intensity was measured using excitation and emission wavelengths of 487 nm and 509 nm, respectively, and expressed as a percentage of that measured in the EmGFP lysates. (D–F) The component of fluorescence attributable to EmGFP was calculated by subtracting the background level of fluorescence (i.e. the autofluorescence detected in lysates of non-injected oocytes) from that measured for each of the oocyte types. In all panels, the data are the mean + SEM of 3–7 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. ns, no significant difference (p > 0.05) from the positive control (one-way ANOVAs).
	Supplementary Figure 8. Detection of the HAEL2-AmDAT and HAEL2-AmDATΔex3 proteins in oocyte membrane preparations. A cropped version of this figure is presented in Figure 5C. The samples were separated on a SDS-polyacrylamide gel and probed with a mouse anti-HA antibody. Bands corresponding to the predicted sizes of AmDAT and AmDATΔex3 were detected in samples prepared from oocytes expressing HAEL2-AmDAT or HAEL2-AmDATΔex3, respectively, and were absent from the samples prepared from non-injected (ni) oocytes. Two protein bands appeared in the lower half of the western blot image; the presence of these bands in all oocyte samples indicates they are endogenous oocyte proteins that reacted non-specifically with the primary or secondary antibody. The image is representative of > 3 independent experiments (performed using oocytes from different frogs).
	Supplementary Figure 9. Total protein levels in the western blot analyses of oocytes co-expressing AmDAT and AmDATΔex3. (A) A representative image depicting the total protein present in samples prepared from oocytes co-expressing HAEL2-AmDAT with AmDATΔex3, EmGFP, or PfNT1, and from oocytes co-expressing AmDAT and HAEL2-AmDATΔex3. Non-injected oocytes (ni) were included as a negative control and oocytes expressing HAEL2-AmDAT served as the positive control. Preparations of oocyte membrane proteins were separated on a SDS polyacrylamide gel and transferred to a nitrocellulose membrane. The proteins were visualised with the MemCodeTM reversible protein stain kit and the image is representative of n = 8. (B,C) The amount of protein present in each lane was semi-quantified using Image Studio Lite and the resulting values were expressed as a percentage of that measured for the HAEL2-AmDAT lane. Total protein levels are shown as the mean + SEM from 3–8 independent experiments performed on days 1 and 3 post-cRNA-injection. ns, no significant difference (p > 0.05) from the positive control (one-way ANOVAs).
	Figure S10. qPCR analysis of amdat and amdat∆ex3 expression in various situations. More details in Supplementary Materials.
	Figure S11. In situ hybridization showing the localization of the amdat transcript in the honey bee brain (adult worker). Dopamine interneurones somata clusters are indicated by arrows. See Supplementary Material for more details.
	FIGURE 1. The honey bee dopamine transporter (AmDAT). (A) amdat gene model showing the exon and intron junctions of the full-length transcript and its spliced variant, the positions of methylated CpGs (black lollipops), and the regions of four amplicons (top) used for methylation analysis (see the main text and Supplementary Material for more details). The only methylated CpG uncovered by whole-genome methylomics is in exon 11. Protein coding exons are shown in green. (B) The predicted topologies of AmDAT (643 residues; shown in blue) and its splice variant AmDATΔex3 (598 residues; shown in orange). AmDATΔex3 lacks transmembrane domain 2 (TMD2) as well as the following cytosolic loop, resulting in an elongated TMD3. The affected region is shaded dark orange. The orientation of the N-terminus and TMD1 are predicted by TMpred and SPOCTOPUS to be inverted relative to the full-length protein.
	FIGURE 2. Heterologous expression of AmDAT and AmDATΔex3 in Xenopus oocytes. (A) Detection of HAEL2-AmDAT (∼55 kDa band indicated by black arrow) and HAEL2-AmDATΔex3 (∼50 kDa band indicated by black arrow) in oocyte membrane preparations. The samples were prepared on day 3 post-cRNA-injection, separated on a SDS-polyacrylamide gel, and probed with a mouse anti-HA antibody. A preparation of membrane protein from non-injected oocytes (ni) probed with the anti-HA antibody did not produce a band within this region. The image is representative of >3 independent experiments (performed using oocytes from different frogs). (B) Semi-quantification of the HAEL2-AmDAT and HAEL2-AmDATΔex3 proteins in the oocyte membrane. The intensity of the HAEL2-AmDATΔex3 band was expressed as a percentage of the band measured for HAEL2-AmDAT. The data are shown as the mean + SEM from six independent experiments (performed using oocytes from different frogs), within which measurements were averaged from two replicates. (C) Immunofluorescence microscopy of Xenopus oocytes expressing HAEL2-AmDAT or HAEL2-AmDATΔex3. The oocyte plasma membrane lies over a band of granules known as the “pigment layer”. This layer in turn surrounds a cytoplasm packed with yolk sacs and small endosomal- and lysosomal-type organelles. The expression of HAEL2-AmDAT resulted in a fluorescent band external to the pigment layer, consistent with this protein being present in the oocyte plasma membrane. A fluorescent band was not detected in non-injected oocytes or in oocytes expressing HAEL2-AmDATΔex3, suggesting that the splice variant is retained at an intracellular membrane. The images are representative of at least two independent experiments (performed using oocytes from different frogs), within which images were obtained from a minimum of 3 oocytes per oocyte type. (D) Transport of dopamine via AmDAT and HAEL2-AmDAT. Measurements of [3H]dopamine uptake by oocytes expressing the non-tagged or HA-tagged forms of AmDAT or AmDATΔex3 were performed on day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as the negative control. Dopamine uptake was expressed as a percentage of that measured in oocytes expressing AmDAT. The data are the mean + SEM of 3–4 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. The capacities of HAEL2-AmDAT and HAEL2-AmDATΔex3 for dopamine transport did not differ significantly from those of their non-tagged counterparts (p > 0.05), consistent with the HA-tag exerting little or no effect upon the functions of these proteins. ∗∗∗denotes a significant difference (p < 0.001) between the indicated treatments (one-way ANOVA).
	FIGURE 3. Transport properties of AmDAT in Xenopus oocytes. Measurements were conducted with oocytes expressing AmDAT on day 3 post-cRNA-injection. The oocytes were held at a membrane potential of –50 mV and superfused with ND96 (pH 7.4) or ND96 (pH 7.4) containing different monoamines at a final concentration of 100 μM. Each bar represents the mean and SEM of n = 11 oocytes (using oocytes from at least two different frogs). The data were normalised to the current induced by 100 μM dopamine. ∗∗∗denotes a significant difference (p < 0.001) from the dopamine current at 100 μM (one-way ANOVA). (A) Substrate specificity of AmDAT. (B) Inhibition of AmDAT by cocaine.
	FIGURE 4. AmDATΔex3 downregulates the AmDAT-mediated uptake of dopamine in Xenopus oocytes. Measurements of [3H]dopamine transport were performed on (A) day 1, (B) day 2, and (C) day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as a negative control, EmGFP and PfNT1 were included as co-injection controls, and oocytes expressing AmDAT served as the positive control. Dopamine uptake was expressed as a percentage of that measured in the AmDAT-expressing oocytes. The component of [3H]dopamine transport attributable to AmDAT was calculated by subtracting the background level of accumulation (i.e., dopamine uptake in non-injected oocytes) from that measured for each of the other oocyte types (the total levels of [3H]dopamine uptake are presented in Supplementary Figure S4). In all panels, the data are the mean + SEM of 3–10 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. ∗∗∗ denotes a significant difference (p < 0.001) from the positive control (one-way ANOVA).
	FIGURE 5. AmDATΔex3 downregulates AmDAT protein levels in Xenopus oocytes. The AmDAT-mediated transport of [3H]dopamine in oocytes expressing the HA-tagged forms of AmDAT or AmDATΔex3 was measured on (A) day 1 and (B) day 3 post-cRNA-injection. Non-injected oocytes (ni) were included as a negative control, EmGFP and PfNT1 were included as co-injection controls, and oocytes expressing AmDAT served as the positive control. Dopamine uptake was expressed as a percentage of that measured in the AmDAT-expressing oocytes. In both panels, the data are the mean + SEM of 3–6 independent experiments (performed using oocytes from different frogs), within which measurements were made from 10 oocytes per treatment. The capacity of HAEL2-AmDAT for dopamine transport, and the ability of HAEL2-AmDATΔex3 to downregulate AmDAT, did not differ significantly from that of its non-tagged counterpart (p > 0.05), consistent with the HA-tag exerting little or no effect upon the functions of these proteins. (C) Detection of the HAEL2-AmDAT (∼55 kDa band indicated by black arrow) and HAEL2-AmDATΔex3 (∼50 kDa band indicated by black arrow) proteins in oocyte membrane preparations. These western blot analyses were performed pairwise with the transport assays presented in panel (A). The samples were separated on a SDS-polyacrylamide gel and probed with a mouse anti-HA antibody. The image is representative of >3 independent experiments (performed using oocytes from different frogs) and is shown in full in Supplementary Figure S8. Semi-quantification of the (D,E) HAEL2-AmDAT and (F,G) HAEL2-AmDATΔex3 proteins in the oocyte membrane preparations was performed on day 1 panels (D,F) and day 3 panels (E,G) post-cRNA-injection. Protein band intensities were expressed as a percentage of that measured for the relevant positive control (i.e., oocytes expressing either HAEL2-AmDAT or HAEL2-AmDATΔex3). The data in panels (D–G) are shown as the mean + SEM from 3–8 independent experiments. ∗∗∗ denotes a significant difference (p < 0.001) from the relevant positive control (one-way ANOVAs).
	FIGURE 6. Interindividual variability in the expression of the amdat and amdatΔex3 transcripts. RNAs extracted from single brains were used for qPCR evaluation. Ten individuals were analyzed in each experiment. Refer to the Supplementary Material for further details.

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