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Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response.

Che P, Chen Y, Lu R, Peng N, Gannon M, Wyss JM, Jiao K, Wang Q - PLoS ONE (2015)

Bottom Line: In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced.These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response.Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Boulevard, Birmingham, AL 35294, United States of America.

ABSTRACT
The α2 adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α2A subtype elicits a hypotensive response whereas the α2B subtype mediates a hypertensive effect that counteracts the hypotensive response by the α2A subtype. We have previously shown that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the α2BAR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α2BAR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 α2BAR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining α2BAR signaling. Consistent with this notion, our in vivo study reveals that the α2BAR-elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α2AAR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

No MeSH data available.


Related in: MedlinePlus

The α2BAR dependent hypertensive response is enhanced in arrestin 3 deficient mice.(A) Mean arterial pressure (MAP) measured in Arr3-/-and corresponding Arr3+/+ mice in the same genetic background after injection of UK14,304 (0.1mg/kg i.v.). (B) Quantitation of agonist-induced changes in MAP(ΔMAP) over the basal level. (C) Quantitation of area under curve of the hypertensive response curve. n = 5 for each group. *, p <0.05, Arr3+/+vs. Arr3-/-.
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pone.0135030.g008: The α2BAR dependent hypertensive response is enhanced in arrestin 3 deficient mice.(A) Mean arterial pressure (MAP) measured in Arr3-/-and corresponding Arr3+/+ mice in the same genetic background after injection of UK14,304 (0.1mg/kg i.v.). (B) Quantitation of agonist-induced changes in MAP(ΔMAP) over the basal level. (C) Quantitation of area under curve of the hypertensive response curve. n = 5 for each group. *, p <0.05, Arr3+/+vs. Arr3-/-.

Mentions: We then compared the level of increase in blood pressure induced by UK14,304 in Sp-/- and the corresponding WT (Sp+/+) mice in the same genetic background. UK14,304-induced change in MAP in Sp+/+ mice were somewhat higher than that in Arr3+/+ mice (7.4 ± 2.5 vs 5.4 ± 2.9, p = 0.28), likely due to the difference in genetic background between these lines. In Sp-/- mice, the α2BAR-elicited hypertensive response was greatly diminished (Fig 8A and 8B) and the AUC in these mice was dramatically reduced as compared to those in Sp+/+ mice (Fig 8C). These data strongly suggest that the in vivo α2BAR responsiveness requires the presence of spinophilin; in mice without spinophilin expression, the α2BAR cannot elicit an effective hypertensive response to α2 ligands.


Spinophilin Is Indispensable for the α2B Adrenergic Receptor-Elicited Hypertensive Response.

Che P, Chen Y, Lu R, Peng N, Gannon M, Wyss JM, Jiao K, Wang Q - PLoS ONE (2015)

The α2BAR dependent hypertensive response is enhanced in arrestin 3 deficient mice.(A) Mean arterial pressure (MAP) measured in Arr3-/-and corresponding Arr3+/+ mice in the same genetic background after injection of UK14,304 (0.1mg/kg i.v.). (B) Quantitation of agonist-induced changes in MAP(ΔMAP) over the basal level. (C) Quantitation of area under curve of the hypertensive response curve. n = 5 for each group. *, p <0.05, Arr3+/+vs. Arr3-/-.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526467&req=5

pone.0135030.g008: The α2BAR dependent hypertensive response is enhanced in arrestin 3 deficient mice.(A) Mean arterial pressure (MAP) measured in Arr3-/-and corresponding Arr3+/+ mice in the same genetic background after injection of UK14,304 (0.1mg/kg i.v.). (B) Quantitation of agonist-induced changes in MAP(ΔMAP) over the basal level. (C) Quantitation of area under curve of the hypertensive response curve. n = 5 for each group. *, p <0.05, Arr3+/+vs. Arr3-/-.
Mentions: We then compared the level of increase in blood pressure induced by UK14,304 in Sp-/- and the corresponding WT (Sp+/+) mice in the same genetic background. UK14,304-induced change in MAP in Sp+/+ mice were somewhat higher than that in Arr3+/+ mice (7.4 ± 2.5 vs 5.4 ± 2.9, p = 0.28), likely due to the difference in genetic background between these lines. In Sp-/- mice, the α2BAR-elicited hypertensive response was greatly diminished (Fig 8A and 8B) and the AUC in these mice was dramatically reduced as compared to those in Sp+/+ mice (Fig 8C). These data strongly suggest that the in vivo α2BAR responsiveness requires the presence of spinophilin; in mice without spinophilin expression, the α2BAR cannot elicit an effective hypertensive response to α2 ligands.

Bottom Line: In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced.These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response.Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, 1918 University Boulevard, Birmingham, AL 35294, United States of America.

ABSTRACT
The α2 adrenergic receptor (AR) subtypes are important for blood pressure control. When activated, the α2A subtype elicits a hypotensive response whereas the α2B subtype mediates a hypertensive effect that counteracts the hypotensive response by the α2A subtype. We have previously shown that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin mice, this response is highly potentiated. In this study, we demonstrate that spinophilin impedes arrestin-dependent phosphorylation and desensitization of the α2BAR subtype by competing against arrestin binding to this receptor subtype. The Del301-303 α2BAR, a human variation that shows impaired phosphorylation and desensitization and is linked to hypertension in certain populations, exhibits preferential interaction with spinophilin over arrestin. Furthermore, Del301-303 α2BAR-induced ERK signaling is quickly desensitized in cells without spinophilin expression, showing a profile similar to that induced by the wild type receptor in these cells. Together, these data suggest a critical role of spinophilin in sustaining α2BAR signaling. Consistent with this notion, our in vivo study reveals that the α2BAR-elicited hypertensive response is diminished in spinophilin deficient mice. In arrestin 3 deficient mice, where the receptor has a stronger binding to spinophilin, the same hypertensive response is enhanced. These data suggest that interaction with spinophilin is indispensable for the α2BAR to elicit the hypertensive response. This is opposite of the negative role of spinophilin in regulating α2AAR-mediated hypotensive response, suggesting that spinophilin regulation of these closely related receptor subtypes can result in distinct functional outcomes in vivo. Thus, spinophilin may represent a useful therapeutic target for treatment of hypertension.

No MeSH data available.


Related in: MedlinePlus