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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 diminished in spinophilin deficient mice.(A) Mean arterial pressure (MAP) measured in Sp+/+ and Sp-/- mice in the same genetic background after UK14,304 injection (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, Sp+/+vs. Sp-/-.
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pone.0135030.g009: The α2BAR dependent hypertensive response is diminished in spinophilin deficient mice.(A) Mean arterial pressure (MAP) measured in Sp+/+ and Sp-/- mice in the same genetic background after UK14,304 injection (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, Sp+/+vs. Sp-/-.

Mentions: We previously found that multiple in vivo responses elicited by the α2AAR subtype are potentiated in spinophilin deficient mice, but dampened in arrestin 3 deficient mice where spinophilin binding to the receptor is enhanced [7, 9, 10]. Particularly, we have found that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin mice, this response is highly potentiated [9]. This is the opposite of what we have observed for responses elicited by the α2BAR subtype in the current study. In spinophilin mice, the α2BAR-elicited hypertensive response was nearly abolished (Fig 9), whereas in arrestin 3 deficient mice, this response was enhanced and prolonged (Fig 8). Our current data suggest that interaction with spinophilin is indispensable for α2BAR to elicit the hypertensive response. Collectively, our previous and current studies suggest that spinophilin regulation of the closely related α2AR subtypes can result in distinct functional outcomes in vivo. Diminished regulation by spinophilin enhances the hypotensive effect elicited by the α2A subtype [9] while reducing the counteracting hypertensive effect by the α2B subtype (Fig 9). Hence, reducing spinophilin binding to the α2AR subtypes may represent a useful therapeutic strategy for treatment of hypertension. This strategy may be particularly beneficial to the hypertensive population with the spinophilin-biased variation of α2BAR, Del301-303, given the essential role of spinophilin in sustaining signaling by this receptor variant (Fig 7C and 7D).


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 diminished in spinophilin deficient mice.(A) Mean arterial pressure (MAP) measured in Sp+/+ and Sp-/- mice in the same genetic background after UK14,304 injection (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, Sp+/+vs. Sp-/-.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526467&req=5

pone.0135030.g009: The α2BAR dependent hypertensive response is diminished in spinophilin deficient mice.(A) Mean arterial pressure (MAP) measured in Sp+/+ and Sp-/- mice in the same genetic background after UK14,304 injection (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, Sp+/+vs. Sp-/-.
Mentions: We previously found that multiple in vivo responses elicited by the α2AAR subtype are potentiated in spinophilin deficient mice, but dampened in arrestin 3 deficient mice where spinophilin binding to the receptor is enhanced [7, 9, 10]. Particularly, we have found that spinophilin attenuates the α2AAR-dependent hypotensive response; in spinophilin mice, this response is highly potentiated [9]. This is the opposite of what we have observed for responses elicited by the α2BAR subtype in the current study. In spinophilin mice, the α2BAR-elicited hypertensive response was nearly abolished (Fig 9), whereas in arrestin 3 deficient mice, this response was enhanced and prolonged (Fig 8). Our current data suggest that interaction with spinophilin is indispensable for α2BAR to elicit the hypertensive response. Collectively, our previous and current studies suggest that spinophilin regulation of the closely related α2AR subtypes can result in distinct functional outcomes in vivo. Diminished regulation by spinophilin enhances the hypotensive effect elicited by the α2A subtype [9] while reducing the counteracting hypertensive effect by the α2B subtype (Fig 9). Hence, reducing spinophilin binding to the α2AR subtypes may represent a useful therapeutic strategy for treatment of hypertension. This strategy may be particularly beneficial to the hypertensive population with the spinophilin-biased variation of α2BAR, Del301-303, given the essential role of spinophilin in sustaining signaling by this receptor variant (Fig 7C and 7D).

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