TY - JOUR
T1 - Dopamine acutely stimulates Na+/H+ exchanger (NHE3) endocytosis via clathrin-coated vesicles
T2 - Dependence on protein kinase A-mediated NHE3 phosphorylation
AU - Hu, Ming C
AU - Fan, Lingzhi
AU - Crowder, Ladonna A.
AU - Karim-Jimenez, Zoubida
AU - Murer, Heini
AU - Moe, Orson W
PY - 2001/7/20
Y1 - 2001/7/20
N2 - Dopamine (DA) is a key hormone in mammalian sodium homeostasis. DA induces natriuresis via acute inhibition of the renal proximal tubule apical membrane Na+/H+ exchanger NHE3. We examined the mechanism by which DA inhibits NHE3 in a renal cell line. DA acutely decreases surface NHE3 antigen in dose- and time-dependent fashion without altering total cellular NHE3. Although DA1 receptor agonist alone decreases surface NHE3, simultaneous DA2 agonist synergistically enhances the effect of DA1. Decreased surface NHE3 antigen, caused by stimulation of NHE3 endocytosis, is dependent on intact functioning of the GTPase dynamin and involves increased binding of NHE3 to the adaptor protein AP2. DA-stimulated NHE3 endocytosis can be blocked by pharmacologic or genetic protein kinase A inhibition or by mutation of two protein kinase A target serines (Ser-560 and Ser-613) on NHE3. We conclude that one mechanism by which DA induces natriuresis is via protein kinase A-mediated phosphorylation of proximal tubule NHE3 leading to endocytosis of NHE3 via clathrin-coated vesicles.
AB - Dopamine (DA) is a key hormone in mammalian sodium homeostasis. DA induces natriuresis via acute inhibition of the renal proximal tubule apical membrane Na+/H+ exchanger NHE3. We examined the mechanism by which DA inhibits NHE3 in a renal cell line. DA acutely decreases surface NHE3 antigen in dose- and time-dependent fashion without altering total cellular NHE3. Although DA1 receptor agonist alone decreases surface NHE3, simultaneous DA2 agonist synergistically enhances the effect of DA1. Decreased surface NHE3 antigen, caused by stimulation of NHE3 endocytosis, is dependent on intact functioning of the GTPase dynamin and involves increased binding of NHE3 to the adaptor protein AP2. DA-stimulated NHE3 endocytosis can be blocked by pharmacologic or genetic protein kinase A inhibition or by mutation of two protein kinase A target serines (Ser-560 and Ser-613) on NHE3. We conclude that one mechanism by which DA induces natriuresis is via protein kinase A-mediated phosphorylation of proximal tubule NHE3 leading to endocytosis of NHE3 via clathrin-coated vesicles.
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U2 - 10.1074/jbc.M011338200
DO - 10.1074/jbc.M011338200
M3 - Article
C2 - 11328806
AN - SCOPUS:0035920227
SN - 0021-9258
VL - 276
SP - 26906
EP - 26915
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 29
ER -