beta1-Adrenergic receptor signaling activates the epithelial calcium channel, transient receptor potential vanilloid type 5 (TRPV5), via the protein kinase A pathway #MMPMID24828496
van der Hagen EA; Tudpor K; Verkaart S; Lavrijsen M; van der Kemp A; van Zeeland F; Bindels RJ; Hoenderop JG
J Biol Chem 2014[Jun]; 289 (26): 18489-96 PMID24828496show ga
Epinephrine and norepinephrine are present in the pro-urine. beta-Adrenergic receptor (beta-AR) blockers administered to counteract sympathetic overstimulation in patients with congestive heart failure have a negative inotropic effect, resulting in reduced cardiac contractility. Positive inotropes, beta1-AR agonists, are used to improve cardiac functions. Active Ca(2+) reabsorption in the late distal convoluted and connecting tubules (DCT2/CNT) is initiated by Ca(2+) influx through the transient receptor potential vanilloid type 5 (TRPV5) Ca(2+) channel. Although it was reported that beta-ARs are present in the DCT2/CNT region, their role in active Ca(2+) reabsorption remains elusive. Here we revealed that beta1-AR, but not beta2-AR, is localized with TRPV5 in DCT2/CNT. Subsequently, treatment of TRPV5-expressing mouse DCT2/CNT primary cell cultures with the beta1-AR agonist dobutamine showed enhanced apical-to-basolateral transepithelial Ca(2+) transport. In human embryonic kidney (HEK293) cells, dobutamine was shown to stimulate cAMP production, signifying functional beta1-AR expression. Fura-2 experiments demonstrated increased activity of TRPV5 in response to dobutamine, which could be prevented by the PKA inhibitor H89. Moreover, nonphosphorylable T709A-TRPV5 and phosphorylation-mimicking T709D-TRPV5 mutants were unresponsive to dobutamine. Surface biotinylation showed that dobutamine did not affect plasma membrane abundance of TRPV5. In conclusion, activation of beta1-AR stimulates active Ca(2+) reabsorption in DCT2/CNT; an increase in TRPV5 activity via PKA phosphorylation of residue Thr-709 possibly plays an important role. These data explicate a calciotropic role in addition to the inotropic property of beta1-AR.
|Animals[MESH]
|Calcium Channels/genetics/*metabolism[MESH]
|Calcium/metabolism[MESH]
|Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics/*metabolism[MESH]
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J+Biol+Chem 2014 ; 289 (26): 18489-96
